Materiały źródłowe

• #1 Acute Lymphocytic Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459149/

  Acute lymphocytic leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a characteristic disease pattern. […] The etiology of acute lymphocytic leukemia is unknown. However, certain environmental factors have been implicated in the etiology of Acute Lymphocytic Leukemia, such as exposure to benzene, ionizing radiation, or previous exposure to chemotherapy or radiotherapy. […] Genomic studies have noted that somatic, polymorphic variants of ARD5B, IKZF1 (the gene encoding Ikaros), and CDKN2A are associated with an increased risk of ALL (odds ratio 1.3 to 1.9). Other rare germline mutations in PAX5, ETV6, and particularly p53 can also strongly predispose to the development of leukemia. […] Acute lymphocytic leukemia is thought to occur after damage to DNA causes lymphoid cells to undergo uncontrolled growth and spread throughout the body.

• #2 Acute lymphoblastic leukemia – Wikipedia

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

  Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. […] The underlying mechanism involves multiple genetic mutations that results in rapid cell division. […] Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. […] Acute lymphoblastic leukemia results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes. […] The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of the disease.

• #3 Acute lymphoblastic leukemia: a comprehensive review and 2017 update | Blood Cancer Journal

  https://www.nature.com/articles/bcj201753

  The pathogenesis of ALL involves the abnormal proliferation and differentiation of a clonal population of lymphoid cells. […] Studies in the pediatric population have identified genetic syndromes that predispose to a minority of cases of ALL, such as Down syndrome, Fanconi anemia, Bloom syndrome, ataxia telangiectasia and Nijmegen breakdown syndrome. […] Other predisposing factors include exposure to ionizing radiation, pesticides, certain solvents or viruses such as Epstein-Barr Virus and Human Immunodeficiency Virus. […] However, in the majority of cases, it appears as a de novo malignancy in previously healthy individuals. Chromosomal aberrations are the hallmark of ALL, but are not sufficient to generate leukemia. […] Characteristic translocations include t(12;21) [ETV6-RUNX1], t(1;19) [TCF3-PBX1], t(9;22) [BCR-ABL1] and rearrangement of MLL.

• #4 Childhood Acute Lymphoblastic Leukemia – NCI

  https://www.cancer.gov/types/leukemia/patient/child-all-treatment-pdq

  Possible genetic risk factors for ALL include: Down syndrome, neurofibromatosis type 1, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia, Li-Fraumeni syndrome (TP53 gene), constitutional mismatch repair deficiency (mutations in certain genes that stop DNA from repairing itself, which leads to the growth of cancers at an early age), having certain changes in chromosomes or genes. […] Other possible risk factors for ALL include: being exposed to x-rays before birth, being exposed to radiation, past treatment with chemotherapy. […] The prognosis depends on: how quickly and how low the leukemia cell count drops after the first month of treatment, your child’s age at the time of diagnosis, sex, race, and ethnic background, the number of white blood cells in the blood at the time of diagnosis, whether the leukemia cells began from B lymphocytes or T lymphocytes, whether there are certain changes in the chromosomes or genes of the leukemia cells, whether your child has Down syndrome, whether leukemia cells are found in the cerebrospinal fluid at diagnosis, your child’s weight at the time of diagnosis and during treatment.

• #5 Acute Lymphoblastic Leukemia (ALL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/207631-overview

  The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations or abnormalities of chromosome number. […] These aberrant lymphoblasts proliferate, reducing the number of the normal marrow elements that produce other blood cell lines (red blood cells, platelets, and neutrophils). Consequently, anemia, thrombocytopenia, and neutropenia occur, although typically to a lesser degree than is seen in acute myeloid leukemia. Lymphoblasts can also infiltrate outside the marrow, particularly in the liver, spleen, and lymph nodes, resulting in enlargement of the latter organs.

• #5 Acute Lymphoblastic Leukemia (ALL): Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/207631-overview

  A proposed mechanism for some cases of childhood ALL is a two-step process of genetic mutation and exposure to infection. […] A review of the genetics, cell biology, immunology, and epidemiology of childhood leukemia by Greaves concluded that B-cell precursor ALL has a multifactorial etiology, with a two-step process of genetic mutation and exposure to infection playing a prominent role. The first step occurs in utero, when fusion gene formation or hyperdiploidy generates a covert, pre-leukemic clone. The second step is the postnatal acquisition of secondary genetic changes that drive conversion to overt leukemia. […] The second step is triggered by infection. Triggering is more likely to occur in children whose immune response is abnormally regulated because they were not exposed to infections in the first few weeks and months of life. Lack of exposure to these early infections, which prime the immune system, is more likely to occur in societies that are zealous about hygiene; this would help explain why at present, pediatric ALL is seen primarily in industrialized societies.

• #6 Pathogenesis of pediatric B‑cell acute lymphoblastic leukemia: Molecular pathways and disease treatments (Review)

  https://www.spandidos-publications.com/10.3892/ol.2020.11583

  Bcell acute lymphoblastic lymphoma (BALL) is a disease found mainly in children and in young adults. BALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL1, RAS and PI3K) leading to dysregulated cell cycle. […] In recent years, cytosolic signal transduction and molecular abnormality have been shown to play important roles in the pathogenesis of B-ALL; the abnormalities include gene mutations, abnormal protein interaction, unarrested cell cycle and increased autophagy. […] The occurrence of B-ALL is known to correlate with a series of gene mutations, which often start at the pluripotent stem cell stage, followed by processes of clonal expansion, differentiation, cell proliferation and dysregulated cell apoptosis; the end result is the replacement of normal lymphoid cells by malignant cells.

• #7 Pathogenesis and prognostication in acute lymphoblastic leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4108947/

  ALL genomes typically harbor fewer structural genetic alterations than many solid tumors. More than 50 recurring regions of DNA copy number alterations have been identified, which are commonly focal deletions, limited to one or few genes involved in normal lymphoid development: transcriptional regulators of lymphoid development (PAX5, IKZF1, EBF1, LEF1), tumor suppressors (CDKN2A, CDKN2B, RB1, TP53), lymphoid signaling genes (BTLA, CD200 TOX), transcriptional regulators and coactivators (TBL1XR1, ERG), as well as regulators of chromatin structure and epigenetic regulators (CTCF, CREBBP). T-lineage ALL is characterized by activating mutations of NOTCH1 and rearrangements of transcription factors TLX1 (HOX11), TLX3 (HOX11L2), LYL1, TAL1, and MLL. […] Sequencing of the full spectrum of ALL subtypes has shown that the alteration of multiple cellular pathways, including cytokine receptor and Ras signaling, tumor suppression, lymphoid development, and epigenetic regulation, are typical events in different ALL subtypes.

• #7 Pathogenesis and prognostication in acute lymphoblastic leukemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4108947/

  The process of lymphoid maturation is tightly controlled by the hierarchical activation of transcription factors and selection through functional signal transduction. Acute lymphoblastic leukemia (ALL) represents a group of B/T-precursor-stage lymphoid cell malignancies arising from genetic alterations that block lymphoid differentiation and drive aberrant cell proliferation and survival. […] ALL represents a group of B/T-precursor-stage lymphoid cell malignancies (arising from genetic insults) that blocks lymphoid differentiation and drives aberrant cell proliferation and survival. The clinical heterogeneity of the disease course and outcome, especially when comparing pediatric and adult populations, reflects different biological subtypes. […] It has long been known that ALL is characterized by gross numerical and structural chromosomal abnormalities, including hyperdiploidy (50 chromosomes), hypodiploidy (44 chromosomes), translocations t{[12;21], [1;19], [9;22], [4;11]} and rearrangements (MYC, MLL). However, several observations indicate that these lesions alone are insufficient to induce leukemia and cooperating lesions are required. As an example, rearrangements such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia.

• #8 What is acute lymphoblastic leukaemia (ALL)? | Cancer Research UK

  https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about

  In acute lymphoblastic leukaemia, the bone marrow makes too many B or T lymphocytes. These lymphocytes are not fully developed and are not able to work normally. They are often known as blast cells. They grow and divide quickly. […] These abnormal cells build up in the bone marrow and stop healthy blood cells from developing. They also spill out into the blood and can spread into other parts of the body. […] Philadelphia positive leukaemia is when you have a particular change in the chromosome of the leukaemia cells. Philadelphia positive ALL happens when a gene called the ABL1 on chromosome 9 breaks off and sticks to a gene called the BCR on chromosome 22. It produces a new gene called BCR-ABL1 which causes the cell to make too much of a protein called tyrosine kinase. This protein encourages leukaemia cells to grow and multiply.

• #9 Acute lymphoblastic leukemia: a comprehensive review and 2017 update | Blood Cancer Journal

  https://www.nature.com/articles/bcj201753

  More recently, a variant with a similar gene expression profile to (Philadelphia) Ph-positive ALL but without the BCR-ABL1 rearrangement has been identified. […] In more than 80% of cases of this so-called Ph-like ALL, the variant possesses deletions in key transcription factors involved in B-cell development including IKAROS family zinc finger 1 (IKZF1), transcription factor 3 (E2A), early B-cell factor 1 (EBF1) and paired box 5 (PAX5). […] Similarly, kinase-activating mutations are seen in 90% of the Ph-like ALL. […] The most common of these include rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3 and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. […] This has significant therapeutic implications as it suggests that Ph-like ALL, which tends to carry a worse prognosis, may respond to kinase inhibitors.

• #10 Acute lymphoblastic leukemia: a comprehensive review and 2017 update | Blood Cancer Journal

  https://www.nature.com/articles/bcj201753

  In fact, Roberts et al. showed that cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R and PDGFRB were sensitive in vitro and in vivo human xenograft models to second-generation TKIs (for example, dasatinib.); those with EPOR and JAK2 rearrangements were sensitive to JAK kinase inhibitors (for example, ruxolitinib); and those with ETV6-NTRK3 fusion were sensitive to ALK inhibitors crizotinib. […] Furthermore, Holmfeldt et al. recently described the genetic basis of another subset with poor outcomes, hypodiploid ALL. […] In near-haploid (24-31 chromosomes) ALL, alterations in tyrosine kinase or Ras signaling was seen in 71% of cases and in IKAROS family zinc finger 3 (IKZF3) in 13% of cases. […] In contrast, low-hypodiploid (32-39 chromosomes) ALL, alterations in p53 (91%), IKZF2 (53%) and RB1 (41%) were more common. […] Both near-haploid and low-hypodiploid exhibited activation of Ras- and PI3K-signaling pathways, suggesting that these pathways may be a target for therapy in aggressive hypodiploid ALL.

• #11 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  The Acute lymphoblastic leukemia (ALL), it produced as a result of a process of malignant transformation of a progenitor lymphocytic cell in the B and T lineages. In ALL, the majority of the cases, the transformation affects the B lineage cells. […] The molecular alterations that are required for the development of a malignant disease is a rare phenomenon when one considers the large number of target cells susceptible to this condition, in other words, a single genetic change rarely be sufficient for developing a malignant tumor. This means that a small percentage of people (1%) who develop malignant hematological disease, probably only 1 cell mutated in a critical gene for the proliferation, differentiation and survival of progenitor cells. There is evidence supporting a sequential multistep process, of alterations in several oncogenes in tumor suppressor genes or microRNA genes in cancerigen cells.

• #12 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  Genetic factors of acute leukemia have been extensively studied. The results of studies of gene expression analysis of high resolution whole genome, copy number alterations of DNA, loss of heterozygosity epigenetic changes and whole genome sequencing, have allowed the recognition of new genetic alterations, so that virtually all patients with ALL can be classified according to the specific genetic abnormality. This information has increased our knowledge of leukemogenesis, the prognosis and has served as the basis for the development of the target therapy. However, the understanding of how genetic alterations collaborate to induce leukemic transformation remains unclear. […] The altered genes in the leukemia can be result in loss or gain of the function through several mechanisms, for example: abnormal recombination (chromosomal, translocation, inversion, insertion) loss of genetic material (deletion) gain of genetic material (duplication) point mutation and the presence additional copies of certain chromosomes as in the case of hyperdiploidy; previous alterations favoring the activation of oncogenes, this encode proteins that control cells proliferation, apoptosis or both.

• #13 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  In this way one can conclude that the pathophysiology of ALL involved mechanisms genetic and environmental complex at different levels, and also have a close and complex relationship. The key features in the pathophysiology of the ALL is its monoclonal origin, uncontrolled cell proliferation by sustained self-stimulation of their receptors for growth, no response to inhibitory signals, and cellular longevity conditioned by decreased apoptosis.

• #14 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

  https://www.intechopen.com/chapters/44045

  When an oncogen is activated by mutation, encoded protein is structurally modified so that enhances its transforming activity, thus remains on active status, continuously transmitting signals through the binding of tyrosine and treonina cinasa. These signals induce cell growth continued incessant. This mechanism of activation of ocogenes is more evident in others forms of leukemia, for example: severe myeloblastic leukemia and other myelodysplastic syndromes where the genes NRAS are mutated. […] There are mutations that suppress the function and are observe in tumor suppressor genes such as TP53, however, less than 3% of patients with ALL are TP53 mutations, although all cells have a resistance abnormal apoptosis induced by lack of significant proportion of p53, which is explained in large part by epigenetic medications.

• #15 Pathogenesis of pediatric B‑cell acute lymphoblastic leukemia: Molecular pathways and disease treatments (Review)

  https://www.spandidos-publications.com/10.3892/ol.2020.11583

  The two hits hypothesis has been proposed to explain the tumorigenesis of childhood ALL. Specifically, the TEL-AML1 fusion gene is a mutation that could be present years before any clinical symptom appears, and often the mutation has taken place earlier in utero. […] The ABL gene on chromosome 9 switches location with the BCR gene on chromosome 22 to form the BCR-ABL fusion gene. […] Patients with ALL and poor prognosis or relapses often have mutations in the RAS pathways; these mutations frequently occur during chemotherapy and are present in clones of relapsed leukemic cells. […] The PI3K/Akt signaling pathway is involved in cell proliferation and cell survival. […] Deregulated cell cycles are correlated with the development of B-ALL. Uncontrolled proliferation of HSC and immature lymphoblastic cells can lead to leukemogenesis.

• #16 A molecular look at the RAS/RAF/MEK/ERK pathway in pediatric acute lymphocytic leukemia (ALL) – MedCrave online

  https://medcraveonline.com/MOJCSR/a-molecular-look-at-the-rasrafmekerk-pathway-in-pediatric-acute-lymphocytic-leukemia-all.html

  Pediatric leukemia is a multifactorial disease with an unknown etiology but can be treated. Just like many other types of cancer, genetic changes take place in leukemia. These genetic lesions, which are effective in the activation of oncogenes or inactivation of tumor suppressor genes; could lead to the development of leukemia via disruptions in the mechanisms regulating cell death, cellular differentiation or division. […] The molecular basis of pediatric leukemia is still not fully understood and scientists believe that there are still many leukemia subgroups that have not yet been classified. […] RAS/RAF/MEK/ERK pathway, which is believed to be important in the development of leukemia, affects many important cellular processes such as cell growth, division, transformation, metabolism control, cell migration, inflammation and apoptosis by controlling the transcription of many genes in almost all eukaryotic organisms. […] Point mutations, deletions and chromosomal translocations, which cause deteriorations in the RAS/RAF/MEK/ERK pathway signaling is among the causes of Leukemia pathogenesis.

• #17

  https://link.springer.com/article/10.1007/s10555-020-09848-z

  The IL7R pathway is known to cooperate with the pre-B cell receptor (preBCR) pathway and their interplay is mandatory for the survival of pre-B-cells. […] Studies have shown that one of the key regulators in CNS infiltration via IL15 and ZAP-70 is the mitogen-activated kinase (MAP-kinase) extracellular-signal regulated kinase (ERK). […] Overall, it appears that dormancy represents an important mechanism of persistence and recurrence of ALL in the CNS.

• #18

  https://link.springer.com/article/10.1007/s10555-020-09848-z

  The question of how leukemia cells infiltrate the CNS was initially raised in the early seventies. […] The endothelial blood-brain barrier (BBB), the blood-leptomeningeal barrier (BLMB), and the blood-CSF-barrier (BCSFB) are considered most relevant. […] In vivo studies with patient derived xenograft (PDX)-ALL cells in mice conducted in the last years collectively found that the brain parenchyma is rarely infiltrated by ALL cells and that if this happens, it occurs mostly in the final stages of CNS leukemia. […] It therefore appears more likely that leukemia cells enter the CNS via the BLMB or the BCSFB. […] When entering the leptomeninges, ALL cells encounter a hostile microenvironment with diminished oxygen and nutrient supply. […] Cytokines such as interleukin (IL)15 and IL7 are involved in lymphocyte development and are highly abundantly present in the CNS.

• #19 A causal mechanism for childhood acute lymphoblastic leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/s41568-018-0015-6

  In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6) runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. […] Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations.

• #20 Landmark paper sets out ‘unified theory’ for cause of acute lymphoblastic leukemia – Oncology Central

  https://www.oncology-central.com/landmark-paper-sets-out-unified-theory-for-cause-of-acute-lymphoblastic-leukemia/

  A landmark paper has outlined, for the first time, a possible cause of most cases of childhood leukemia, following more than a century of controversy about its origins. […] In this study, the team of researchers assessed the most comprehensive body of evidence ever collected on acute lymphoblastic leukemia (ALL). […] They discovered that ALL arises through a two-step process of genetic mutation and exposure to infection, which means that it may be preventable with treatments to stimulate or prime the immune system in infancy. […] The first step involves a genetic mutation that predisposes children to leukemia, this mutation occurs in the fetus. […] The second step is triggered in childhood when the child is exposed to one or more common infections, primarily in infants who have experienced clean childhoods in the first year of life without much interaction with other infants or older children.

• #21 A causal mechanism for childhood acute lymphoblastic leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/s41568-018-0015-6

  Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. […] This study models the link between infections and activation of secondary genetic changes in ALL via RAG and AID.

• #22 Acute lymphoblastic leukemia: an overview of etiology, epidemiology, pathophysiology, diagnosis, and treatment

  https://lymphoblastic-hub.com/medical-information/acute-lymphoblastic-leukemia-an-overview-of-etiology-epidemiology-pathophysiology-diagnosis-and-treatment/

  B-ALL results from a series of genetic mutations followed by clonal expansion, differentiation, cell proliferation, and dysregulated cell apoptosis. The molecular pathways involved in B-ALL pathogenesis are detailed in Figure 3. […] The pathogenesis of T-ALL is characterized by the accumulation of multiple genetic mutations altering cell growth, differentiation, proliferation, and survival; these include deregulation of oncogenic NOTCH1 signaling, cell cycle, increased activation of kinase signaling, transcriptional alterations of oncogenes or tumor-suppressor genes, alterations in ribosomal function and translation, and deregulation of epigenetic regulators.

• #23 Homo sapiens diseses – B-cell acute lymphoblastic leukemia (B-ALL)

  https://www.ufrgs.br/imunovet/molecular_immunology/pathohomotissueblood_BALL.html

  translocations : […] AML1 / RUNX1-ETV6 fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. […] minor BCR-ABL1 fusions (encoding P190 BCR/c-ABL) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. […] The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. […] In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population. […] ETV6-Janus kinase 2 (JAK2) : somatically acquired R683 JAK2 mutations define a distinct B-ALL subgroup that is uniquely associated with trisomy 21.

• #24 Case Study: Prognostic Factors in Acute Lymphocytic Leukemia – Hematology.org

  https://www.hematology.org/education/trainees/fellows/case-studies/acute-lymphocytic-leukemia

  NOTCH1 is a gene that encodes for a transmembrane receptor that regulates normal T-cell development. This mutation has been detected in gt; 50 percent of both pediatric and adult T-ALL cases. FBXW7 encodes an E3 ubiquitin ligase responsible for negative regulation of NOTCH1 signaling. Mutations involving FBXW7 occur at a frequency of about 20 percent in ALL. Pediatric studies suggest the good prognostic value of NOTCH1/ FBXW7 mutations. The results in adult ALL patients are less clear, with conflicting results. […] Isocitrate Dehydrogenase 1(IDH1) is a gene located in chromosome 2q33.3, while IDH2 is located in chromosome 15q26.1. These genes are responsible for encoding enzymes that catalyze the oxidative decarboxylation of isocitrate to -ketoglutarates. Intact IDH activity is necessary for normal cellular protection from oxidative stress. These mutations were first described in low-grade gliomas/secondary glioblastomas and subsequently in acute myeloid leukemia. Some studies suggest that mutations involving this gene may confer poor prognosis in certain subsets, particularly in cytogenetically normal FMS-like tyrosine kinase-3 (Flt-3), wild-type, and nucleophosmin-1 (NPM-1)-mutated AML.

• #25 Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

  https://www.mdpi.com/2072-6694/13/7/1536

  Studies conducted in a recent decade revealed that acute lymphoblastic leukemia cells exploit various mechanisms to avoid immune recognition and destruction by the immune system. […] As a consequence, leukemia cells become more resistant to treatment, which results in poor patient outcomes. […] Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. […] Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. […] We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system.

• #26 Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

  https://www.mdpi.com/2072-6694/13/7/1536

  We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. […] An immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions. […] Cancer cells can avoid recognition and elimination by the immune system by various, cancer type-specific mechanisms, which are already well documented in solid tumors and are just being discovered in ALL. […] Downregulation or loss of human leukocyte antigen (HLA) class I molecules, which leads to impaired recognition of leukemic cells by cytotoxic T lymphocytes, is a rare but functionally significant mechanism of immune evasion in ALL.

• #27 Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

  https://www.mdpi.com/2072-6694/13/7/1536

  Moreover, recent data uncovers the mechanism of T cell exhaustion operating in ALL, opening the possibility to employ appropriate immune checkpoint inhibitors to ALL treatment protocols. […] The overview of the mutual interactions between ALL cells and the key cells of the BM microenvironment is presented in Figure 1. […] We also discuss how various elements of the BM niche affect ALL chemo- and immunotherapy and present recently discovered treatment strategies that restore or stimulate the immune response to ALL.

• #28

  https://link.springer.com/article/10.1007/s10555-020-09848-z

  Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. […] The specific mechanisms and molecules fostering CNS disease in ALL are widely unknown. Here, we will highlight the mechanisms and molecular background of CNS disease in ALL based on recent findings.

• #29

  https://omim.org/entry/613065

  In mice, Yao et al. (2018) showed that ALL cells in the circulation are unable to breach the blood-brain barrier; instead, they migrate into the central nervous system (CNS) along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin (see 150320), which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor alpha-6 integrin (ITGA6; 147556) is expressed in most cases of ALL. Yao et al. (2018) found that alpha-6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3K-delta (PIK3CD; 602839) inhibitor, which decreased alpha-6 integrin expression on ALL cells, or specific alpha-6 integrin-neutralizing antibodies, and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid, and CNS disease symptoms despite minimally decreased bone marrow disease burden. Yao et al. (2018) concluded that alpha-6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

• #30 Potential role of short-chain fatty acids in the pathogenesis and management of acute lymphocytic leukemia

  https://atm.amegroups.org/article/view/119520/html

  Acute lymphocytic leukemia (ALL) is an aggressive hematological malignancy of highly proliferative lymphoblasts. […] Since epigenetic modifications are dominantly reversible, epidrugs (drugs targeting epigenetic markers) are considered for feasibility in the treatment of ALL as epigenetic modifications, and acetylation of histones was demonstrated to play a critical role in the pathogenesis of ALL. […] Histone deacetylases (HDACs) have been shown to be differentially expressed in several hematological malignancies, including ALL. […] Overexpression of HDACs have been associated with poor prognosis in ALL, as it leads to impaired cell development and uncontrolled growth via cyclin-dependent kinase inhibitor protein inhibition. […] A naturally occurring HDACi are short-chain fatty acids (SCFAs), such as butyrate and propionate.

• #31 Potential role of short-chain fatty acids in the pathogenesis and management of acute lymphocytic leukemia

  https://atm.amegroups.org/article/view/119520/html

  SCFAs exert their effect through three mechanisms of action: (I) by HDAC inhibition via HDACs 1-11 and sirtuins; (II) via GPR41/43 G-protein coupled receptors; and (III) via GPR109A receptors impacting lymphocyte chemotaxis. […] We and other groups have shown that ALL is characterized by an altered gut microbiota and low SCFA levels, including butyrate, propionate, and acetate. […] It has been shown that levels of butyrate, propionate, and acetate significantly decrease in ALL, and replenishing these SCFAs ameliorate the consequences of the disease. […] An intriguing hypothesis would be to assert that the depletion of natural HDACi may participate in the pathophysiological development of lymphocytes and in the pathogenesis of ALL. […] SCFAs have very selective inhibitory capacity for HDACs, which could circumvent the limited efficacy of pan-HDACs, such as Givinostat, seen in the treatment of ALL.

• #32 Acute Lymphoblastic Leukemia (ALL) | Leukemia and Lymphoma Society

  https://www.lls.org/research/acute-lymphoblastic-leukemia-all

  Acute lymphoblastic leukemia (ALL) is a malignant transformation and proliferation of white blood cells called lymphocytes. The hallmark of ALL involves chromosomal abnormalities and genetic alterations associated with differentiation and proliferation of the malignant cells. […] About 25 percent of adults and about 3 percent of children have an ALL subtype called Ph-positive ALL (Ph+). In Ph+ ALL, a translocation between chromosomes 9 and 22 leads to the abnormal BCR-ABL fusion gene that makes an abnormal protein that helps leukemia cells to grow. […] The developmental landscape of T-ALL is ripe for further exploration. LLS is funding a number of grants that delve into the novel pathways of this disease and look to better understand how the disease is driven while also developing novel therapeutics.

• #33 What is acute lymphoblastic leukaemia (ALL)? | Cancer Research UK

  https://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about

  In Philadelphia chromosome positive leukaemia an abnormal change happens to chromosomes 9 and 22. Part of chromosome 9 breaks off where the gene ABL1 is located and part of chromosome 22 breaks off where the BCR gene is located. The broken parts swap places creating a new gene on chromosome 22. […] This new gene tells the cell to make a large quantity of a protein called tyrosine kinase which encourages leukaemia cells to grow. […] There are targeted cancer drugs that can block the protein and stop the leukaemia from growing. These drugs are called tyrosine kinase blockers.

• #34 Acute Lymphoblastic Leukemia (ALL) | Leukemia and Lymphoma Society

  https://www.lls.org/research/acute-lymphoblastic-leukemia-all

  Response patterns to blinatumomab, a type of antibody therapy that forms a bridge between the cytotoxic T cells and the tumor cells, are essentially binary, with some patients having a striking response, and others showing no response at all, despite adequate expression of the targeted protein, CD19, on the leukemia cells. […] MLL defects occur in 70% and 10% of infants and adults, respectively, with ALL. Rearrangements to the MLL gene result in some of the most aggressive leukemias in both children and adults. […] This subtype comprises up to 25% of B-ALL and is characterized by a diverse range of genetic alterations activating kinase signaling pathways and poor outcome.

• #35 New Targeted Therapy in Acute Lymphocytic Leukemia: A Review of Blinatumomab in Relapsed/Refractory Acute Lymphocytic Leukemia

  https://www.targetedonc.com/view/new-targeted-therapy-in-acute-lymphocytic-leukemia-a-review-of-blinatumomab-in-relapsed-refractory-acute-lymphocytic-leukemia

  Blinatumomab has emerged as a novel and effective salvage treatment for adult patients with relapsed or refractory B-ALL, a population with limited treatment options and a dismal prognosis. Allogeneic HSCT is the only potentially curative treatment but is associated with significant morbidity and mortality, particularly in patients who are elderly, with comorbidities, and/or with resistant or high-risk disease. Historically, 30%-45% of patients experience a CR with first salvage therapy consisting of high-dose combination chemotherapy; this percentage is significantly lower with each subsequent salvage and is associated with significant mortality. […] Blinatumomab has a notable effect on inducing MRD-negativity, in both the salvage and upfront settings. More than 80% of patients with relapsed/refractory B-ALL achieved MRD negativity in the salvage setting, which correlated with a longer RFS and OS. Additionally, in an earlier blinatumomab phase II trial, 21 adult patients with ALL in CR after induction and consolidation therapy, but with MRD positivity, were treated with blinatumomab in the front-line setting. Of the 20 evaluable patients, 80% achieved MRD negativity within 4 cycles. […] While the risk of CRS and neurologic toxicities is significant, incorporating a dexamethasone prephase and vigilant monitoring during initiation have significantly reduced the risk of severe toxicities without knowingly compromising efficacy.

• #36

  https://haematologica.org/article/view/1150

  Accumulating evidence clearly indicates that molecular characterisation at diagnosis represents the most relevant prognostic information for risk stratification of the patients at diagnosis. […] Finally, our progress in understanding the relationships between genetic lesions and environmental etiologic agents will further contribute to delineating the natural history of pediatric ALL.

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