Materiały źródłowe

• #1 The Pathogenesis of Chronic Lymphocytic Leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4144790/

  Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5+CD23+ B cells in blood, marrow, and second lymphoid tissues. Gene-expression profiling and phenotypic studies suggest that CLL is probably derived from CD5+ B cells similar to those found in the blood of healthy adults. Next-generation sequencing has revealed recurrent genetic lesions that are implicated in CLL pathogenesis and/or disease progression. The biology of CLL is entwined with its microenvironment, in which accessory cells can promote leukemia cell growth and/or survival. Recently, much attention has been focused on the CLL B cell receptor (BCR) and on chemokine receptors that enable CLL cells to home to lymphoid tissues and to establish the leukemia microenvironment. Agents that can interfere with BCR signaling or chemokine receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in patients with this disease.

• #2

  https://haematologica.org/article/view/9796

  Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. […] In the last decade, genomic and epigenomic studies have expanded our knowledge of the pathogenesis of CLL remarkably, unraveling a large number of novel alterations that might drive the evolution of the disease. Moreover, understanding the crosstalk between tumor cells and their microenvironment has been fundamental in the development of new, targeted agents, which are transforming the way we manage the disease.

• #3 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The cells of origin in most cases of CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes. […] CLL B-lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20dim, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone of lymphoid follicles, B-cell CLL is most likely a malignancy of a mantle zonebased subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies. […] CLL B-lymphocytes express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

• #4 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The cells of origin in most cases of CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes. […] CLL B-lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20dim, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone of lymphoid follicles, B-cell CLL is most likely a malignancy of a mantle zonebased subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies. […] CLL B-lymphocytes express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

• #5

  https://link.springer.com/article/10.1007/s12185-014-1651-6

  Unlike normal HSCs, HSCs from CLL patients gave rise to monoclonal or oligoclonal mature B cells that simulated monoclonal B cell lymphocytosis (MBL), the preleukemic state of CLL, after xenogeneic transplantation. […] These results indicated that in CLL, HSCs possess the cell-intrinsic propensity to generate clonal CLL-like B cells. […] Therefore, when we consider the pathogenesis of mature lymphoid malignancies, particularly in elderly individuals, the effects of HSC aging should be taken into account in some, if not all, mature lymphoid malignancies. […] Our hypothesis regarding CLL development has been schematized in Fig. 1. […] These findings strongly suggested that the propensity to generate clonal B cells has already been acquired at the HSC stage. […] These studies have suggested that self-renewing HSCs may be a common target for oncogenic events in human hematological malignancies, including both mature lymphoid malignancies and myeloid neoplasms.

• #6 The Pathogenesis of Chronic Lymphocytic Leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4144790/

  Our understanding of pathological mechanism(s) involved in CLL may have implications for the development of new treatments. […] This review focuses on recent advances in our understanding of factors governing the pathogenesis and progression of CLL that have been made through analyses of leukemia cell gene expression and next-generation sequencing. Insights gained through these studies are guiding the development of targeted therapies that may be more effective and better tolerated than currently available treatments for patients with CLL. […] CLL cells commonly harbor deletions at 13q14, 11q22q23, or 17p13 or may have an extra copy of chromosome 12 (trisomy 12); such genetic alterations are significantly associated with clinical outcome. The advent of next-generation sequencing technologies, coupled with gene copy-number analyses, have identified additional genetic lesions in CLL, such as mutations in NOTCH1, SF3B1, and BIRC3. Such mutations could be used as potential therapeutic targets or as biomarkers that can distinguish among patients who may have disparate clinical outcomes.

• #7

  https://haematologica.org/article/view/9796

  Many studies have confirmed the fundamental role of BCR activation for CLL pathogenesis. Several proteins, including phosphatidylinositol 3 kinase (PI3K), Bruton tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) are essential for BCR signal transduction. The effect of BCR-mediated signaling varies according to IGHV mutation status: M-CLL cells are generally driven towards anergy, whereas U-CLL cells are more directed towards cell growth and proliferation. […] Initial chromosome banding analysis revealed that deletions or trisomies were relatively common but only observed in fewer than half of the patients. With the advent of fluorescent in situ hybridization (FISH), genomic aberrations were identified in more than 80% of patients, the more relevant being trisomy 12, 13q deletion [del(13q)], 11q deletion [del(11q)] and 17p deletion [del(17p)]; and FISH became the gold standard for genomic evaluation in CLL.

• #8 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The proto-oncogene Bcl2 is overexpressed in B-cell CLL. The proto-oncogene Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of Bcl-2 protein, genetic translocations that are known to result in the overexpression of Bcl2, such as t(14;18), are not found in patients with CLL. Analysis of the molecular pathophysiology of CLL allows the development of therapies that target leukemic cells with these genetic changes. Venetoclax, which is one of the first-line treatment options for CLL, is designed to block the Bcl2 protein. […] Studies have shown that this upregulation in Bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA). These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

• #9

  https://www.jci.org/articles/view/64101

  Karyotypic investigations revealed the association of CLL with del13q14, trisomy 12, del11q22-q23, and del17p13. The advent of next-generation sequencing (NGS) technologies, coupled with gene copy number analysis, has enabled exploration of the CLL genome, uncovering genetic lesions that recurrently target this leukemia. […] Del13q14 is the most frequent alteration and occurs in 50%60% of cases. Because this lesion is found at a similar frequency in MBL and is often detectable as a single lesion, this alteration may represent an early event in the disease. […] Recently, whole exome sequencing studies have revealed recurrent genetic lesions that affect genes implicated in different biological pathways of potential pathogenetic relevance for CLL. These genes include NOTCH1, splicing factor 3b, subunit 1 (SF3B1), BIRC3, and myeloid differentiation primary response gene 88 (MYD88).

• #10 Chronic Lymphocytic Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470433/

  In CLL, CD5+ B cells are continuously activated by mutations leading to MBL. The accumulation of genetic abnormalities in more mature B cells causes a clonal division of the neoplastic B-cell within the lymph nodes. […] These neoplastic B cells escape apoptosis and continue to divide over time within the lymph nodes. They then infiltrate the spleen and bone marrow, causing splenomegaly and hypercellular bone marrow (on bone marrow biopsy). […] The deletion/point mutation of TP53 leads to CLL. 11q chromosome contains the ataxia-telangiectasia mutated (ATM) gene. ATM kinase is responsible for the delayed progression of the cell cycle in the presence of DNA damage, allowing the cell to repair the damage.

• #11 Recurrent Genomic Aberrations in Chronic Lymphocytic Leukaemia – Implications for Disease Pathogenesis and Prognosis – touchONCOLOGY

  https://touchoncology.com/haematological-malignancies/journal-articles/recurrent-genomic-aberrations-in-chronic-lymphocytic-leukaemia-implications-for-disease-pathogenesis-and-prognosis/

  Importantly, deletions in 11q and in particular 17p were associated with poor clinical outcome, while, by contrast, patients with deletion of 13q as a sole abnormality were found to have a favourable clinical course. […] The prognostic relevance of 11q deletions in CLL was initially reported in the mid-1990s, when patients carrying this deletion were shown to have progressive disease and reduced survival. […] In CLL, loss of 17p is associated with the worst survival and shortest TTT, as well as treatment failure with purine nucleoside analogues and alkylating agents. […] In multivariate analysis of prognostic markers in CLL, deletion of 17p has repeatedly been shown to be one of the strongest independent markers of clinical outcome. […] Thus, while genomic complexity is clinically relevant, FISH analysis of recurrent genomic aberrations would in most cases identify the poor-prognosis cases.

• #12 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in over 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. […] Deletion of 11q and 17p as well as trisomy 12 have also been reported, albeit less commonly. The presence of trisomy 12, which is observed in 15% of CLL patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival. 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

• #13 Recurrent Genomic Aberrations in Chronic Lymphocytic Leukaemia – Implications for Disease Pathogenesis and Prognosis – touchONCOLOGY

  https://touchoncology.com/haematological-malignancies/journal-articles/recurrent-genomic-aberrations-in-chronic-lymphocytic-leukaemia-implications-for-disease-pathogenesis-and-prognosis/

  Importantly, deletions in 11q and in particular 17p were associated with poor clinical outcome, while, by contrast, patients with deletion of 13q as a sole abnormality were found to have a favourable clinical course. […] The prognostic relevance of 11q deletions in CLL was initially reported in the mid-1990s, when patients carrying this deletion were shown to have progressive disease and reduced survival. […] In CLL, loss of 17p is associated with the worst survival and shortest TTT, as well as treatment failure with purine nucleoside analogues and alkylating agents. […] In multivariate analysis of prognostic markers in CLL, deletion of 17p has repeatedly been shown to be one of the strongest independent markers of clinical outcome. […] Thus, while genomic complexity is clinically relevant, FISH analysis of recurrent genomic aberrations would in most cases identify the poor-prognosis cases.

• #14 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in over 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. […] Deletion of 11q and 17p as well as trisomy 12 have also been reported, albeit less commonly. The presence of trisomy 12, which is observed in 15% of CLL patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival. 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

• #15

  https://haematologica.org/article/view/9796

  On average, CLL tumors accumulate around 2,500 somatic mutations with a clear difference between MCLL and U-CLL (3,000 vs. 2,000 somatic mutations on average, respectively). This increased mutation burden observed in M-CLL has limited transformation potential as patients with M-CLL have fewer mutated drivers and better clinical outcomes than patients with U-CLL. […] Deep, targeted next-generation sequencing has revealed that subclonal mutations (i.e., those present in only a fraction of tumor cells) can be detected for all driver genes and are associated with rapid disease progression and poor outcome. This is particularly relevant for TP53 mutations given the fact that, as explained below, CLL therapy is based on the presence or absence of these mutations. […] The genome of CLL features widespread hypomethylation, and a large fraction of the differences between UCLL and M-CLL can be attributed to their different cell of origin in germinal center-independent or -experienced B cells, respectively. Major hypomethylation changes occur at transcription factor binding sites such as TCF3, PU.1/SPIB, NFAT and EGR, and enhancers that modulate genes relevant for CLL pathogenesis involved in B-cell function, BCR signaling, and NF-B activation among others.

• #16 Insights into genetic aberrations and signalling pathway interactions in chronic lymphocytic leukemia: from pathogenesis to treatment strategies | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-024-00710-w

  The results of recent studies utilizing WES and WGS on large datasets have significantly advanced our understanding of the biological underpinnings of CLL and its molecular subtypes. […] The emergence of targeted therapies has profoundly modified the prognostic implications, particularly concerning TP53 aberrations and IGHV mutation status. […] The advent of targeted therapies has significantly improved patient outcomes, and the effectiveness of these targeted therapies has shifted the focus from genetic profiling to clinical outcomes. […] Despite these advancements, TP53 aberrations continue to exert a deleterious influence on the prognosis of patients with CLL undergoing chemoimmunotherapy, underscoring the critical role of genetic markers in the stratification and selection of therapeutic strategies.

• #17 Insights into genetic aberrations and signalling pathway interactions in chronic lymphocytic leukemia: from pathogenesis to treatment strategies | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-024-00710-w

  CLL is considered a BCR-dependent disease because BCR signalling is constitutively activated and constitutes an important biological feature of CLL cells, including CLL cell survival. […] The involvement of BCR signalling in CLL is substantiated by evidence that CLL cells rely on BCR signalling for disease progression. This is further supported by the success of inhibitors targeting BCR-associated kinases, which suggests a crucial role for BCR signalling in the progression of CLL. […] CLL heavily depends on BCR signalling for its pathogenesis, including the avoidance of apoptosis, promotion of proliferation, and cell activation. […] The BCR is linked to a network of kinases and scaffold proteins tethered to the plasma membrane to regulate BCR activation, forming a signalosome after antigen binding.

• #18

  https://haematologica.org/article/view/9796

  The B-cell receptor (BCR) is crucial for CLL pathogenesis and is composed of immunoglobulin (IG) molecules plus CD79a/b subunits. From an immunogenetic point of view, two major molecular subgroups have been identified: those harboring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, 98% identity with the germline) and those with mutated IGHV genes (MCLL). U-CLL originates from B cells that have not experienced the germinal center, whereas M-CLL originates from post-germinal center B cells. […] CLL cells are highly dependent on signals coming from the microenvironment for proliferation and survival. Tumor cells proliferate primarily in lymph nodes, and to less extent in bone marrow, where they are in intimate contact with extracellular matrix, T cells, nurse-like cells, follicular dendritic cells and other stromal cells. The interactions between CLL cells and this complex microenvironment are mediated by a network of adhesion molecules, cell surface ligands, chemokines, cytokines, and their respective receptors.

• #19

  https://haematologica.org/article/view/9796

  The B-cell receptor (BCR) is crucial for CLL pathogenesis and is composed of immunoglobulin (IG) molecules plus CD79a/b subunits. From an immunogenetic point of view, two major molecular subgroups have been identified: those harboring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, 98% identity with the germline) and those with mutated IGHV genes (MCLL). U-CLL originates from B cells that have not experienced the germinal center, whereas M-CLL originates from post-germinal center B cells. […] CLL cells are highly dependent on signals coming from the microenvironment for proliferation and survival. Tumor cells proliferate primarily in lymph nodes, and to less extent in bone marrow, where they are in intimate contact with extracellular matrix, T cells, nurse-like cells, follicular dendritic cells and other stromal cells. The interactions between CLL cells and this complex microenvironment are mediated by a network of adhesion molecules, cell surface ligands, chemokines, cytokines, and their respective receptors.

• #20 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  Chronic lymphocytic leukemia (CLL) is one of the most common forms of leukemia that affects adults. […] Over the last decade, the treatment landscape for CLL has significantly changed with the advent of novel targeted therapies. This includes the introduction of Brutons tyrosine kinase (BTK) inhibitors, such as ibrutinib. […] The B-cell receptor (BCR) signaling pathway is essential for B-cell proliferation, differentiation, and apoptosis. BTK is a key enzyme in this pathway. When the BCR is activated by antigen binding, protein tyrosine kinases activate BTK, which then activates phosphatidylinositol 3-kinase (PI3K), converting phosphatidylinositol 4,5bisphosphate (PIP2) into phosphatidylinositol 3,4,5trisphosphate (PIP3). This process promotes intracellular calcium release and triggers key signaling pathways that promote cell proliferation while inhibiting apoptosis.

• #21 The Pathogenesis of Chronic Lymphocytic Leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4144790/

  The tissue microenvironment plays a central role in the pathogenesis of CLL. As mentioned above, whereas the vast majority of circulating CLL cells in blood are nondividing and resting, tissue CLL cells proliferate at a relatively high rate. CLL cell proliferation occurs in microanatomical sites termed proliferation centers or pseudofollicles. Proliferating Ki-67+ CLL cells are in intimate contact with accessory cells, such as T cells, stromal cells of mesenchymal origin, and/or monocyte-derived nurselike cells. Gene-expression studies have found that CLL cells isolated from lymph nodes and, to a lesser extent, the marrow have higher expression of E2F and MYC than do CLL cells in the blood. In such tissues, particularly in the secondary lymphoid tissues, there appears to be enhanced leukemia cell BCR signaling and activation of receptors of the TNF family.

• #22 The Pathogenesis of Chronic Lymphocytic Leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4144790/

  The tissue microenvironment plays a central role in the pathogenesis of CLL. As mentioned above, whereas the vast majority of circulating CLL cells in blood are nondividing and resting, tissue CLL cells proliferate at a relatively high rate. CLL cell proliferation occurs in microanatomical sites termed proliferation centers or pseudofollicles. Proliferating Ki-67+ CLL cells are in intimate contact with accessory cells, such as T cells, stromal cells of mesenchymal origin, and/or monocyte-derived nurselike cells. Gene-expression studies have found that CLL cells isolated from lymph nodes and, to a lesser extent, the marrow have higher expression of E2F and MYC than do CLL cells in the blood. In such tissues, particularly in the secondary lymphoid tissues, there appears to be enhanced leukemia cell BCR signaling and activation of receptors of the TNF family.

• #23 The Pathogenesis of Chronic Lymphocytic Leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4144790/

  The tissue microenvironment plays a central role in the pathogenesis of CLL. As mentioned above, whereas the vast majority of circulating CLL cells in blood are nondividing and resting, tissue CLL cells proliferate at a relatively high rate. CLL cell proliferation occurs in microanatomical sites termed proliferation centers or pseudofollicles. Proliferating Ki-67+ CLL cells are in intimate contact with accessory cells, such as T cells, stromal cells of mesenchymal origin, and/or monocyte-derived nurselike cells. Gene-expression studies have found that CLL cells isolated from lymph nodes and, to a lesser extent, the marrow have higher expression of E2F and MYC than do CLL cells in the blood. In such tissues, particularly in the secondary lymphoid tissues, there appears to be enhanced leukemia cell BCR signaling and activation of receptors of the TNF family.

• #24

  https://haematologica.org/article/view/9796

  The B-cell receptor (BCR) is crucial for CLL pathogenesis and is composed of immunoglobulin (IG) molecules plus CD79a/b subunits. From an immunogenetic point of view, two major molecular subgroups have been identified: those harboring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, 98% identity with the germline) and those with mutated IGHV genes (MCLL). U-CLL originates from B cells that have not experienced the germinal center, whereas M-CLL originates from post-germinal center B cells. […] CLL cells are highly dependent on signals coming from the microenvironment for proliferation and survival. Tumor cells proliferate primarily in lymph nodes, and to less extent in bone marrow, where they are in intimate contact with extracellular matrix, T cells, nurse-like cells, follicular dendritic cells and other stromal cells. The interactions between CLL cells and this complex microenvironment are mediated by a network of adhesion molecules, cell surface ligands, chemokines, cytokines, and their respective receptors.

• #25 Chronic lymphocytic leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia

  As CLL cells accumulate, they begin to promote inflammation and an immunosuppressive environment through the release of different chemical signals. […] CLL is commonly preceded by a pre-cancerous state known as monoclonal B-cell lymphocytosis (MBL). This occurs when there is in an increase in a specific type of white blood cells but the number remains less than 5 billion cells per liter (L) (5×10^9/L) of blood. This subtype, termed chronic lymphocytic leukemia-type MBL (CLL-type MBL) is an asymptomatic, indolent, and chronic disorder in which people exhibit a mild increase in the number of circulating B-cell lymphocytes. These B-cells are monoclonal, which means they are produced by a single ancestral B-cell. They share some of the same cell marker proteins, chromosome abnormalities, and gene mutations that are found in CLL.

• #26 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The proto-oncogene Bcl2 is overexpressed in B-cell CLL. The proto-oncogene Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of Bcl-2 protein, genetic translocations that are known to result in the overexpression of Bcl2, such as t(14;18), are not found in patients with CLL. Analysis of the molecular pathophysiology of CLL allows the development of therapies that target leukemic cells with these genetic changes. Venetoclax, which is one of the first-line treatment options for CLL, is designed to block the Bcl2 protein. […] Studies have shown that this upregulation in Bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA). These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

• #27 Molecular Pathogenesis of Chronic Lymphocytic Leukemia

  https://eurekaselect.com/public/article/2688

  Chronic lymphocytic leukemia (CLL) is unique among malignancies since it represents an accumulation of B-lymphocytes resistant to apoptosis. Several factors are thought to confer this unusual feature to a CLL B-cell. Misbalance between cytoplasmic pro-survival and pro-death molecules, such as Bcl-2, Mcl-1 and alike, appears to be one of the key factors defining B-cell longevity. Autocrine pathways, such as vascular endothelial growth factor-receptor pathway, also contribute to survival. The role of B-cell receptor (BCR) is less straightforward. In the last decade it became clear that CLL does not constitute a uniform disease, but, based on the prevalence of mutations in the BCR heavy chain (IgVH), can be classified into two distinct subgroups. Several molecular markers correlate with IgVH mutations. Some of them, like zeta-chain associated protein kinase, are also involved in BCR signaling and influence cell cycle. Yet the primary pathogenic event leading to increased proliferation and survival in CLL is difficult to ascertain. Molecules involved in BCR signaling pathways and cytoplasmic pro-survival players probably act in concert to confer resistance to apoptosis.

• #28 Apoptosis inducers in chronic lymphocytic leukemia | Oncotarget

  https://www.oncotarget.com/article/1480/text/

  The intrinsic pathway (also known as the mitochondrial pathway) integrates various intracellular signals at the mitochondrial membrane and is regulated by Bcl-2 family proteins (that share at least one of the four Bcl-2 homology domains, BH1 to 4). […] The leukemic cells in the blood are quiescent but are unable to initiate their apoptotic program. This situation is due to several factors including defects in the CLL cells apoptotic machinery and excessive survival signals delivered by the microenvironment. […] Indeed, silencing Mcl-1 with small interfering RNA (siRNA) is enough to induce apoptosis in CLL cells. […] A schematic representation of the impaired apoptotic machinery in CLL cells is shown in Figure 1. […] The Noxa/Mcl-1 axis is an attractive target for apoptosis-based strategies in CLL.

• #29 Chronic Lymphocytic Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470433/

  Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) is an indolent malignancy characterized by increased production of mature but dysfunctional B lymphocytes. CLL/SLL is defined as a monoclonal lymphoproliferative disease characterized by the proliferation and accumulation of morphologically mature but immunologically dysfunctional B-cell lymphocytes that are smudge cells, as noted on peripheral smear. […] The pathogenesis of CLL/SLL is a two-step process that leads to the clonal replication of malignant B lymphocytes. The first step is the development of MBL cells secondary to multiple factors such as antigenic stimulation, genetic mutations, and cytogenetic abnormalities. The second step is the progression of MBL to CLL/SLL by the further insult to the B-cell clone, either due to additional genetic abnormalities or changes in the bone marrow microenvironment. B-cell antigen receptor (BCR) expression induces antigen-independent cell-autonomous signaling, which is an important step in the pathogenesis of CLL.

• #30

  https://haematologica.org/article/view/9796

  CLL is always preceded by an often unnoticed premalignant state known as high-count MBL. Low-count MBL may persist for a long time but the risk of progression is negligible. Yearly, 1% of cases of high-count MBL evolve into CLL requiring therapy, and 2-10% of patients with symptomatic CLL eventually develop Richter transformation. […] Transformation of CLL into an aggressive lymphoma occurs in 2-10% of patients and in most of them (90%) corresponds to a DLBCL, but Hodgkin lymphoma may also occur. The DLBCL usually emerges as a linear evolution of the same CLL clone with only rare cases deriving from a branching divergent subclone.

• #31

  https://haematologica.org/article/view/9796

  CLL is always preceded by an often unnoticed premalignant state known as high-count MBL. Low-count MBL may persist for a long time but the risk of progression is negligible. Yearly, 1% of cases of high-count MBL evolve into CLL requiring therapy, and 2-10% of patients with symptomatic CLL eventually develop Richter transformation. […] Transformation of CLL into an aggressive lymphoma occurs in 2-10% of patients and in most of them (90%) corresponds to a DLBCL, but Hodgkin lymphoma may also occur. The DLBCL usually emerges as a linear evolution of the same CLL clone with only rare cases deriving from a branching divergent subclone.

• #32

  https://haematologica.org/article/view/9796

  On average, CLL tumors accumulate around 2,500 somatic mutations with a clear difference between MCLL and U-CLL (3,000 vs. 2,000 somatic mutations on average, respectively). This increased mutation burden observed in M-CLL has limited transformation potential as patients with M-CLL have fewer mutated drivers and better clinical outcomes than patients with U-CLL. […] Deep, targeted next-generation sequencing has revealed that subclonal mutations (i.e., those present in only a fraction of tumor cells) can be detected for all driver genes and are associated with rapid disease progression and poor outcome. This is particularly relevant for TP53 mutations given the fact that, as explained below, CLL therapy is based on the presence or absence of these mutations. […] The genome of CLL features widespread hypomethylation, and a large fraction of the differences between UCLL and M-CLL can be attributed to their different cell of origin in germinal center-independent or -experienced B cells, respectively. Major hypomethylation changes occur at transcription factor binding sites such as TCF3, PU.1/SPIB, NFAT and EGR, and enhancers that modulate genes relevant for CLL pathogenesis involved in B-cell function, BCR signaling, and NF-B activation among others.

• #33 Chronic lymphocytic leukemia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/symptoms-causes/syc-20352428

  Chronic lymphocytic leukemia (CLL) is a type of cancer of the blood and bone marrow the spongy tissue inside bones where blood cells are made. […] Doctors aren’t certain what starts the process that causes chronic lymphocytic leukemia. What’s known is that something happens to cause changes (mutations) in the DNA of blood-producing cells. A cell’s DNA contains the instructions that tell the cell what to do. The changes tell the blood cells to produce abnormal, ineffective lymphocytes. […] Beyond being ineffective, these abnormal lymphocytes continue to live and multiply when healthy lymphocytes would die. The abnormal lymphocytes accumulate in the blood and certain organs, where they cause complications. They may crowd healthy cells out of the bone marrow and interfere with blood cell production. […] Doctors and researchers are working to understand the exact mechanism that causes chronic lymphocytic leukemia.

• #34 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The proto-oncogene Bcl2 is overexpressed in B-cell CLL. The proto-oncogene Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of Bcl-2 protein, genetic translocations that are known to result in the overexpression of Bcl2, such as t(14;18), are not found in patients with CLL. Analysis of the molecular pathophysiology of CLL allows the development of therapies that target leukemic cells with these genetic changes. Venetoclax, which is one of the first-line treatment options for CLL, is designed to block the Bcl2 protein. […] Studies have shown that this upregulation in Bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA). These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

• #35 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The proto-oncogene Bcl2 is overexpressed in B-cell CLL. The proto-oncogene Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of Bcl-2 protein, genetic translocations that are known to result in the overexpression of Bcl2, such as t(14;18), are not found in patients with CLL. Analysis of the molecular pathophysiology of CLL allows the development of therapies that target leukemic cells with these genetic changes. Venetoclax, which is one of the first-line treatment options for CLL, is designed to block the Bcl2 protein. […] Studies have shown that this upregulation in Bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA). These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

• #36 Chronic Lymphocytic Leukemia (CLL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/199313-overview

  The proto-oncogene Bcl2 is overexpressed in B-cell CLL. The proto-oncogene Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of Bcl-2 protein, genetic translocations that are known to result in the overexpression of Bcl2, such as t(14;18), are not found in patients with CLL. Analysis of the molecular pathophysiology of CLL allows the development of therapies that target leukemic cells with these genetic changes. Venetoclax, which is one of the first-line treatment options for CLL, is designed to block the Bcl2 protein. […] Studies have shown that this upregulation in Bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA). These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

• #37

  https://haematologica.org/article/view/9796

  On average, CLL tumors accumulate around 2,500 somatic mutations with a clear difference between MCLL and U-CLL (3,000 vs. 2,000 somatic mutations on average, respectively). This increased mutation burden observed in M-CLL has limited transformation potential as patients with M-CLL have fewer mutated drivers and better clinical outcomes than patients with U-CLL. […] Deep, targeted next-generation sequencing has revealed that subclonal mutations (i.e., those present in only a fraction of tumor cells) can be detected for all driver genes and are associated with rapid disease progression and poor outcome. This is particularly relevant for TP53 mutations given the fact that, as explained below, CLL therapy is based on the presence or absence of these mutations. […] The genome of CLL features widespread hypomethylation, and a large fraction of the differences between UCLL and M-CLL can be attributed to their different cell of origin in germinal center-independent or -experienced B cells, respectively. Major hypomethylation changes occur at transcription factor binding sites such as TCF3, PU.1/SPIB, NFAT and EGR, and enhancers that modulate genes relevant for CLL pathogenesis involved in B-cell function, BCR signaling, and NF-B activation among others.

• #38 Chronic lymphocytic leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia

  Chronic lymphocytic leukemia (CLL) results from an unusual growth and expansion of white blood cells. This manifestation typically begins with a single hematopoietic stem cell that acquires certain mutations over time that allows it to continue to expand and grow at a faster rate than other cells. Each patient with CLL may be affected by a different set of mutations, making these cells sometimes difficult to target and treat. Some of the most common mutations that have been found in CLL-affected cells include the following: NOTCH1, TP53, ATM, and SF3B1. […] CLL can also be caused by a number of epigenetic changes, which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of three different methyl subgroups (naive B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed. Some relevant genetic mutations may be inherited. Since there is no one single mutation that is associated with CLL in all cases, an individual’s susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of CLL are co-inherited. Up until 2020, 45 susceptibility loci have been identified. Of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling.

• #39

  https://haematologica.org/article/view/9796

  Family studies have consistently shown that first-degree relatives of patients with CLL have a 2- to 8-fold increased risk of developing the disease. Genomewide association studies have identified up to 45 susceptibility loci, mostly mapping to non-coding regions of the genome. The mechanisms linking these susceptibility variants and the development of the disease are being elucidated thanks to integrated genome-wide association/ transcriptome/epigenome studies. […] Hematopoietic stem cells derived from patients with CLL seem epigenetically primed to clonal expansions of CLL-like cells when implanted in mice. Interestingly, these clonal expansions do not always carry the same genomic aberrations as the original disease. Moreover, hematopoietic stem cells derived from patients with CLL express higher levels of transcription factors, such as TCF3, IKZF1 or IRF8, than those from healthy donors, which is intriguing if we consider that some susceptibility loci increase TCF3 binding or IRF8 expression.

• #40

  https://haematologica.org/article/view/9796

  Family studies have consistently shown that first-degree relatives of patients with CLL have a 2- to 8-fold increased risk of developing the disease. Genomewide association studies have identified up to 45 susceptibility loci, mostly mapping to non-coding regions of the genome. The mechanisms linking these susceptibility variants and the development of the disease are being elucidated thanks to integrated genome-wide association/ transcriptome/epigenome studies. […] Hematopoietic stem cells derived from patients with CLL seem epigenetically primed to clonal expansions of CLL-like cells when implanted in mice. Interestingly, these clonal expansions do not always carry the same genomic aberrations as the original disease. Moreover, hematopoietic stem cells derived from patients with CLL express higher levels of transcription factors, such as TCF3, IKZF1 or IRF8, than those from healthy donors, which is intriguing if we consider that some susceptibility loci increase TCF3 binding or IRF8 expression.

• #41 Chronic lymphocytic leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia

  Chronic lymphocytic leukemia (CLL) results from an unusual growth and expansion of white blood cells. This manifestation typically begins with a single hematopoietic stem cell that acquires certain mutations over time that allows it to continue to expand and grow at a faster rate than other cells. Each patient with CLL may be affected by a different set of mutations, making these cells sometimes difficult to target and treat. Some of the most common mutations that have been found in CLL-affected cells include the following: NOTCH1, TP53, ATM, and SF3B1. […] CLL can also be caused by a number of epigenetic changes, which are adaptations that add a tag to specific DNA sequences, rather than altering the sequence itself. In CLL, these changes can be classified into the addition of three different methyl subgroups (naive B-cell-like, memory B-cell-like, and intermediate), which impact how much that DNA sequence is transcribed. Some relevant genetic mutations may be inherited. Since there is no one single mutation that is associated with CLL in all cases, an individual’s susceptibility may be impacted when multiple mutations that are associated with an increase in the risk of CLL are co-inherited. Up until 2020, 45 susceptibility loci have been identified. Of these loci, 93% are linked to the alteration of 30 gene expressions involved in immune response, cell survival, or Wnt signaling.

• #42 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  Chronic lymphocytic leukemia (CLL) is one of the most common forms of leukemia that affects adults. […] Over the last decade, the treatment landscape for CLL has significantly changed with the advent of novel targeted therapies. This includes the introduction of Brutons tyrosine kinase (BTK) inhibitors, such as ibrutinib. […] The B-cell receptor (BCR) signaling pathway is essential for B-cell proliferation, differentiation, and apoptosis. BTK is a key enzyme in this pathway. When the BCR is activated by antigen binding, protein tyrosine kinases activate BTK, which then activates phosphatidylinositol 3-kinase (PI3K), converting phosphatidylinositol 4,5bisphosphate (PIP2) into phosphatidylinositol 3,4,5trisphosphate (PIP3). This process promotes intracellular calcium release and triggers key signaling pathways that promote cell proliferation while inhibiting apoptosis.

• #43 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  Ibrutinib covalently and irreversibly binds to cysteine 481 (C481) in the adenosine triphosphate (ATP)-binding site in the kinase domain of BTK. This inhibits the phosphorylation of downstream kinases in the BCR signaling pathway, subsequently inhibiting cell growth, migration, proliferation, and survival of malignant B cells. Inhibition of BTK has been shown to reduce pro-inflammatory cytokines and chemokines for homing to lymph nodes. Ibrutinib can bind to interleukin (IL)-2-inducible kinase (ITK) in T cells, enhancing tumor immune surveillance. Ibrutinib also targets the CXCR4/SDF1 axis, downregulating CD20 expression on B cells. Finally, BCR signaling blockade through BTK inhibition with ibrutinib may indirectly affect the tumor microenvironment by promoting a pro-apoptotic environment.

• #44 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  Ibrutinib covalently and irreversibly binds to cysteine 481 (C481) in the adenosine triphosphate (ATP)-binding site in the kinase domain of BTK. This inhibits the phosphorylation of downstream kinases in the BCR signaling pathway, subsequently inhibiting cell growth, migration, proliferation, and survival of malignant B cells. Inhibition of BTK has been shown to reduce pro-inflammatory cytokines and chemokines for homing to lymph nodes. Ibrutinib can bind to interleukin (IL)-2-inducible kinase (ITK) in T cells, enhancing tumor immune surveillance. Ibrutinib also targets the CXCR4/SDF1 axis, downregulating CD20 expression on B cells. Finally, BCR signaling blockade through BTK inhibition with ibrutinib may indirectly affect the tumor microenvironment by promoting a pro-apoptotic environment.

• #45 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  The activity of ibrutinib is complementary to venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, allowing for a synergistic treatment combination. Ibrutinib reduces cell surface levels of CXCR4, resulting in CLL cells being released from the spleen and lymph node into the peripheral blood. Ibrutinib also indirectly decreases MCL-1 protein levels, leaving these CLL cells highly dependent on BCL-2 signaling. Venetoclax directly targets BCL-2, resulting in CLL cell apoptosis. […] BTK mutations may prevent the binding of ibrutinib, a key mechanism of resistance, further emphasizing the complementary proapoptotic effects of venetoclax. […] Ibrutinib is an important treatment option for both treatment-nave and R/R patients with CLL. Identifying patients who are most likely to benefit from ibrutinib and consideration of patient-related factors, such as comorbidities and high-risk features, are crucial to optimizing outcomes.

• #46 Fatty Acid Oxidation Inhibition Enhanced PI3K Inhibitor Efficacy in CLL – Hematology Advisor

  https://www.hematologyadvisor.com/news/chronic-leukemia-cll-fatty-acid-oxidation-inhibition-pi3k-treatment-risk/

  A prognostic risk score based on fatty acid metabolism (FAM) gene expression revealed distinct immune phenotypic differences and implicated fatty acid oxidation (FAO) in chronic lymphocytic leukemia (CLL) progression, according to a study published in Biomarker Research. […] The inhibition of FAO impaired CLL cell survival and synergistically enhanced the efficacy of idelalisib, an inhibitor of PI3K. […] These results suggest that metabolic reprogramming of FAO supports CLL progression by shaping an immunosuppressive microenvironment and promoting cell survival. […] FAM modulation might represent a promising immunotherapeutic strategy by reversing the immunosuppressive microenvironment, while inhibition of FAO enhances PI3K inhibitor efficacy through synergistic effects.

• #47 Fatty Acid Oxidation Inhibition Enhanced PI3K Inhibitor Efficacy in CLL – Hematology Advisor

  https://www.hematologyadvisor.com/news/chronic-leukemia-cll-fatty-acid-oxidation-inhibition-pi3k-treatment-risk/

  A prognostic risk score based on fatty acid metabolism (FAM) gene expression revealed distinct immune phenotypic differences and implicated fatty acid oxidation (FAO) in chronic lymphocytic leukemia (CLL) progression, according to a study published in Biomarker Research. […] The inhibition of FAO impaired CLL cell survival and synergistically enhanced the efficacy of idelalisib, an inhibitor of PI3K. […] These results suggest that metabolic reprogramming of FAO supports CLL progression by shaping an immunosuppressive microenvironment and promoting cell survival. […] FAM modulation might represent a promising immunotherapeutic strategy by reversing the immunosuppressive microenvironment, while inhibition of FAO enhances PI3K inhibitor efficacy through synergistic effects.

• #48 Resistance mechanism in chronic lymphocytic leukemia identified – German Cancer Research Center

  https://www.dkfz.de/en/news/press-releases/detail/resistance-mechanism-in-chronic-lymphocytic-leukemia-identified

  Researchers at the German Cancer Research Center (DKFZ) have succeeded in identifying a resistance mechanism that often occurs in a specific targeted therapy against chronic lymphocytic leukemia (CLL). […] The drug ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. These agents, which have only been available for about ten years, have significantly improved the treatment options for chronic lymphocytic leukemia: BTK inhibitors have a targeted effect on the malignant B cells in CLL. […] The enormous adaptability of cancer cells enables them to become resistant to cancer drugs. As a result, the drug loses its therapeutic effect in almost all CLL patients over time, and the disease returns. […] The altered activity of the proteasome during ibrutinib treatment suggests that the breakdown of proteins plays a role in the development of resistance.

• #49 Resistance mechanism in chronic lymphocytic leukemia identified – German Cancer Research Center

  https://www.dkfz.de/en/news/press-releases/detail/resistance-mechanism-in-chronic-lymphocytic-leukemia-identified

  Researchers at the German Cancer Research Center (DKFZ) have succeeded in identifying a resistance mechanism that often occurs in a specific targeted therapy against chronic lymphocytic leukemia (CLL). […] The drug ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. These agents, which have only been available for about ten years, have significantly improved the treatment options for chronic lymphocytic leukemia: BTK inhibitors have a targeted effect on the malignant B cells in CLL. […] The enormous adaptability of cancer cells enables them to become resistant to cancer drugs. As a result, the drug loses its therapeutic effect in almost all CLL patients over time, and the disease returns. […] The altered activity of the proteasome during ibrutinib treatment suggests that the breakdown of proteins plays a role in the development of resistance.

• #50 Resistance mechanism in chronic lymphocytic leukemia identified – German Cancer Research Center

  https://www.dkfz.de/en/news/press-releases/detail/resistance-mechanism-in-chronic-lymphocytic-leukemia-identified

  The proteasome inhibitor carfilzomib led to longer survival in CLL mice with ibrutinib resistance. […] The proteasome inhibitors also worked in cultured human B cells taken from CLL patients who were resistant to ibrutinib. These agents could therefore be an option in the future for the treatment of CLL patients who develop resistance to BTK inhibitors.

• #51 Ibrutinib for CLL: Mechanism of action and clinical considerations

  https://lymphomahub.com/medical-information/ibrutinib-for-cll-mechanism-of-action-and-clinical-considerations

  The activity of ibrutinib is complementary to venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, allowing for a synergistic treatment combination. Ibrutinib reduces cell surface levels of CXCR4, resulting in CLL cells being released from the spleen and lymph node into the peripheral blood. Ibrutinib also indirectly decreases MCL-1 protein levels, leaving these CLL cells highly dependent on BCL-2 signaling. Venetoclax directly targets BCL-2, resulting in CLL cell apoptosis. […] BTK mutations may prevent the binding of ibrutinib, a key mechanism of resistance, further emphasizing the complementary proapoptotic effects of venetoclax. […] Ibrutinib is an important treatment option for both treatment-nave and R/R patients with CLL. Identifying patients who are most likely to benefit from ibrutinib and consideration of patient-related factors, such as comorbidities and high-risk features, are crucial to optimizing outcomes.

• #52 Chronic lymphocytic leukaemia: diagnosis and management  – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/chronic-lymphocytic-leukaemia-diagnosis-and-management

  The pathogenesis of CLL is multifactorial and dependent on various factors, such as B-cell receptor pathway signalling, somatic mutations, genomic mutations and the CLL micro-environment. […] B-cell receptor signalling plays an essential role in pathogenesis of CLL. […] Several cellular components of the CLL micro-environment have been described, along with the signalling pathways involved in CLL homing, survival and proliferation, which now provides a rationale for targeting the CLL micro-environment. […] Understanding the pathogenesis of CLL has a direct correlation with treatment. For example, inhibitors of BCR signalling pathway are now standard of care for first-line and relapsed CLL.

• #53

  https://www.jci.org/articles/view/64101

  Molecular knowledge of the CLL genotype has significantly advanced the understanding of the genetic basis of chemorefractoriness. TP53 disruption predicts treatment failure with many regimens and mandates the use of alternative therapeutic strategies that are more efficacious. […] The high prevalence of TP53 disruption in RS reflects the selection of a chemorefractory clone under the pressure of previous CLL treatments, thus suggesting an explanation for the poor outcome and the limited sensitivity to conventional drugs.

• #54

  https://www.jci.org/articles/view/64101

  Molecular knowledge of the CLL genotype has significantly advanced the understanding of the genetic basis of chemorefractoriness. TP53 disruption predicts treatment failure with many regimens and mandates the use of alternative therapeutic strategies that are more efficacious. […] The high prevalence of TP53 disruption in RS reflects the selection of a chemorefractory clone under the pressure of previous CLL treatments, thus suggesting an explanation for the poor outcome and the limited sensitivity to conventional drugs.

• #55 Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment

  https://www.mdpi.com/2072-6694/16/20/3483

  Chronic Lymphocytic Leukemia (CLL) is the most frequent type of leukemia in Western countries. In recent years, there have been important advances in the knowledge of molecular alterations that underlie the disease’s pathogenesis. Very heterogeneous prognostic subgroups have been identified by the mutational status of immunoglobulin heavy variable genes (IGVH), FISH analysis and molecular evaluation of TP53 mutations. Next-generation sequencing (NGS) technologies have provided a deeper characterization of the genomic and epigenomic landscape of CLL. […] Understanding this heterogeneity is crucial for developing personalized treatment strategies and improving patient outcomes. […] The therapeutic landscape of CLL has significantly evolved in recent years. The use of immunochemotherapy is currently very limited, given the advent of many new biological agents. These novel targeted agents, including Bruton Tyrosine Kinase (BTKi) inhibitors (e.g., ibrutinib, acalabrutinib, and zanubrutinib) and B-cell Lymphoma-2 (BCL-2) inhibitors (e.g., venetoclax) have shown substantial efficacy and improved safety profiles compared to traditional immunochemotherapy. This shift towards targeted treatments has transformed the management of CLL and needs an accurate re-definition of prognostic/predictive parameters.

• #56 Duvelisib Plus Venetoclax Is Active in Relapsed/Refractory CLL and Richter Syndrome

  https://www.onclive.com/view/duvelisib-plus-venetoclax-is-active-in-relapsed-refractory-cll-and-richter-syndrome

  Duvelisib plus venetoclax was shown to be active in relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter syndrome (RS), including in patients with high-risk, TP53-aberrant disease and those who had received prior treatment with BTK inhibitors, according to data from the phase 2 portion of a phase 1/2 trial (NCT03534323) that were presented at the 2024 ASH Annual Meeting. […] The all-oral, minimal residual disease [MRD]driven, time-limited regimen duvelisib plus venetoclax is active in relapsed/refractory CLL and RS, including in high-risk patients with TP53-aberrant disease and [those who received treatment] post-BTK inhibitor, lead study author Jennifer L. Crombie, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said during a presentation of the data. […] Our data support exploration of duvelisib plus venetoclax in larger studies of patients with relapsed/refractory CLL and RS, Crombie concluded during the presentation.

• #57 Secondary immunodeficiency associated with chronic lymphocytic leukaemia (CLL » SID

  https://www.secondaryimmunodeficiency.com/chronic-lymphocytic-leukaemia/

  Chronic Lymphocytic Leukaemia pathogenesis impacts differentiation and function of blood cells. […] CLL cells have an elevated expression of PD-L1 and interact with PD-1 on activated T cells. […] CLL pathogenesis affects differentiation and function of T-cells, B-cells, NK-cells, Monocytes, Neutrophils and Complement. […] CLL results in defective innate and adaptive immunity, increasing the risk for secondary immunodeficiency. […] The severity of hypogammaglobulinaemia and infiltration rate of the bone marrow increase with the duration and progression of disease. […] All Ig classes (Immunoglobulins IgG, IgA, IgM) are involved, leading to increased secondary immune deficiency. […] CLL progression is associated with higher infection rates. […] CLL results in hypogammaglobulinaemia across all Immunoglobulin classes. […] Significant mortality and morbidity due to infections facilitated by CLL itself and by treatment-related adverse events. […] CLL patients have a ~50% increased risk of death due to infection (as contributory or underlying cause) compared to matched control population.

• #58 Molecular pathogenesis of chronic lymphocytic leukemia | Białopiorowicz | Hematology in Clinical Practice

  https://journals.viamedica.pl/hematology_in_clinical_practice/article/view/50440

  Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, characterized by accumulation of mature but functionally incompetent clonal B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. […] The use of novel molecular biology techniques revealed genetic and epigenetic heterogeneity among CLL patients and allowed to define novel somatic mutations of prognostic value. […] The CLL genome and epigenome undergo dynamic changes during disease course due to clonal evolution, which leads to selection and expansion of leukemic clones with the highest survival potential. […] This review focuses on the key aspects of CLL molecular pathogenesis including genetic and epigenetic alterations, B-cell signaling and the role of tumor microenvironment. […] Progress in the understanding of CLL biology will help to develop more accurate prognostication models and enable more personalized patient treatment in the future.

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