Materiały źródłowe

• #1 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. […] 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.

• #1 Pathogenesis and prognostication in acute lymphoblastic leukemia

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

  It is suggested that the initial event confers self-renewal coupled with mutation, leading to developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to establishment of the leukemic clone. […] Advances in genomic techniques over the last two decades have enabled better genetic profiling of the leukemic clone. The techniques used include three main categories. Firstly, cytogenetic studies with conventional G banding as well as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) analysis have identified structural chromosomal alterations. Secondly, genome-wide profiling uses array-based comparative genomic hybridization or single nucleotide polymorphism microarrays and gene expression profiling. Thirdly, sequencing studies use whole-genome sequencing, transcriptome sequencing and/or whole-exome sequencing to more comprehensively define the genomic landscape of these diseases. […] 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.

• #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. […] ALL emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation. […] These changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. […] Chromosomal translocations involve moving a large region of DNA from one chromosome to another. […] The result is a cell that divides more often. […] Acute lymphoblastic leukemia results when enough of these genetic changes are present in a single lymphoblast.

• #3 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 lymphoblastic leukemia is thought to occur after damage to DNA causes lymphoid cells to undergo uncontrolled growth and spread throughout the body.

• #4 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.

• #4 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.

• #5 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. Chromosome 22 with the new fusion gene is referred to as the Philadelphia chromosome. […] 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. PI3K regulates the expression levels of mTOR, Bcl-2, NFB and other proteins that all promote cell proliferation. […] Deregulated cell cycles are correlated with the development of B-ALL. Uncontrolled proliferation of HSC and immature lymphoblastic cells can lead to leukemogenesis. Overexpression of c-MYC protein is associated with accelerated cell cycle progression in B-ALL.

• #6 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. In contrast, most adults with ALL have no identifiable risk factors. […] 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. […] 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. Only 1% of children born with a pre-leukemic clone progress to leukemia.

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

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

  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. […] Cases of ALL with abnormalities of chromosome band 11q23 following treatment with topoisomerase II inhibitors for another malignancy have been described. However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML rather than ALL. […] Routine use of next-generation sequencing and other molecular methods is identifying recurrent genetic abnormalities with prognostic implications.

• #7 A causal mechanism for childhood acute lymphoblastic leukaemia.

  https://repository.icr.ac.uk/items/c8450cdc-e4b3-4489-9ab6-2c4efa736277

  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. Risk is further modified by inherited genetics, chance and, probably, diet. 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. Childhood ALL may be a preventable cancer.

• #8 Acute Lymphoblastic Leukaemia (Symptoms and Treatment)

  https://patient.info/doctor/acute-lymphoblastic-leukaemia-pro

  Patients with trisomy 21 have 10- to 20-fold risk of developing ALL compared with the general population, and other disorders with excessive chromosomal fragility are also associated with higher risks (eg, Fanconi’s anaemia, ataxia with telangiectasia). […] Prenatal chromosomal translocations generate chimeric fusion genes (such as TEL-AML1) that appear to be important but insufficient disease initiators, since they are found in many more neonatal cord blood samples (TEL-AML1 is found in 1% of newborn babies) than in children who eventually develop acute lymphoblastic leukaemia. […] Acute lymphoblastic leukaemia in adults does appear to be related to high doses of radiation (based on studies following survivors of atomic bomb explosions, other exposures such as the Chernobyl accident and therapeutic radiotherapy) but the position with regard to low doses seems less clear.

• #8 Acute Lymphoblastic Leukaemia (Symptoms and Treatment)

  https://patient.info/doctor/acute-lymphoblastic-leukaemia-pro

  Establishing environmental risk factors is difficult due to problems confirming and quantifying exposure, lack of a prospective cohort, confounding variables, etc. […] Insulation from common infections in early life may predispose children to abnormal immune responses when they encounter them later, placing them at higher risk of developing ALL. […] Excess of ALL in rural, potentially immunologically naive communities with 'outbreaks’ triggered by influx of new population (Kinlen’s population mixing theory).

• #9 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. […] 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. […] 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).

• #10 Acute lymphoblastic leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_lymphoblastic_leukemia_pathophysiology

  In leukemias including acute lymphoblastic leukemia, chromosomal translocation occur regularly. It is thought that most translocations occur before birth during fetal development. These translocations may trigger oncogenes to „turn on”, causing unregulated mitosis where cells divide too quickly and abnormally, resulting in leukemia. […] It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including: Hyperdiploidy (50 chromosomes), Hypodiploidy (44 chromosomes), Translocations t{[12;21], [1;19], [9;22], [4;11]}, Rearrangements (MYC, MLL). […] However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved. For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia.

• #10 Acute lymphoblastic leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_lymphoblastic_leukemia_pathophysiology

  T-lineage acute lymphoblastic leukemia is understood as activated mutations of NOTCH1 and rearrangements of transcription factors which are the following TLX1 (HOX11), TLX3 (HOX11L2), LYL1, TAL1, MLL. […] Arrangements of the full range of acute lymphoblastic leukemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following: Cytokine receptor and Ras signaling, Tumor suppression, Lymphoid development, Epigenetic regulation. […] The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

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

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

  Similarly, kinase-activating mutations are seen in 90% of the Ph-like ALL. […] This has significant therapeutic implications as it suggests that Ph-like ALL, which tends to carry a worse prognosis, may respond to kinase inhibitors. […] 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.

• #12 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.

• #13 T-lineage acute lymphoblastic leukemia (T-ALL)

  https://atlasgeneticsoncology.org/haematological/1374/t-lineage-acute-lymphoblastic-leukemia-(t-all)

  Immunophenotypic and gene expression analyses of T-ALL cells have revealed heterogeneity that is partially related to arrest at distinct stages of development. Initial cytogenetics studies of T-ALL cases showed nonrandom breakpoints within the following three T-cell receptor (TCR) gene clusters: TRA@ (TCRA), TRD@ (TCRD) locus (14q11.2), or TRB@ (TCRB) locus (7q34). The TCR breakpoints were present in about 30% to 35% of T-ALL cases. The TRG@ (TCRG) locus (7p14) may be restricted to T-cell ALL in patients with ataxia telangiectasia. During T-cell differentiation, these four loci undergo structural rearrangement that is analogous to the rearrangement of immunoglobulin genes during B-cell development. […] The chromosomal aberrations that affect the TCR loci were among the first to be reported in T-ALL. Subsequently, these and other rarer translocations facilitated the identification of genes that are altered in T-ALL, many of which are also transcriptionally activated without evidence of any detectable chromosomal rearrangement affecting these loci. In summary, the ectopic expression of TAL1(SCL), LYL1, LMO1, LMO2, TLX1(HOX11), and TLX3 (HOX11L2), NOTCH1-activating mutations, and CDKN2-inactivating deletions are among the most prevalent causes of human T-ALL.

• #14 Inside the biology of early T-cell precursor acute lymphoblastic leukemia: the perfect trick | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-021-00347-z

  To date, even if both the transcriptional and mutational landscapes have been extensively described, there is no univocal hypothesis about the leukemogenic patterns of ETP-ALL. […] Approximately 20% of pediatric ETP-ALL cases harbour activating mutations in the interleukin-7 receptor (IL7r) or the downstream Janus kinases JAK1 and JAK3 genes. […] It was demonstrated that Il7r mutants are capable of blocking thymocyte differentiation at the DN2 stage and inducing ETP-ALL in transplanted mice; moreover, the concomitant introduction of Runx1 and Jak3 mutations in hematopoietic stem and progenitor cells in mice gave rise to T-ALL with the ETP phenotype. […] This latter observation opens a therapeutic window for JAK inhibition and suggests that ETP-ALL may require continual IL7r signaling for maintenance and leukemic growth.

• #14 Inside the biology of early T-cell precursor acute lymphoblastic leukemia: the perfect trick | Biomarker Research | Full Text

  https://biomarkerres.biomedcentral.com/articles/10.1186/s40364-021-00347-z

  Inactivating mutations in components of the epigenetic regulator polycomb repressive complex 2 (PRC2), such as EZH2, SUZ12, EED, are frequently detected in ETP-ALL and are associated with aberrant RAS signalling in response to the loss of the H3K27me3 repressive histone mark. […] Concurrent mutation of EZH2 and the transcription factor RUNX1 is a relatively common event in ETP-ALL; experimental data in normal ETP showed that inactivation of either of the two genes did not affect cell development, whereas inactivation of both genes resulted in expansion of the ETP pool and blocked differentiation. […] Coherently, in Runx1/Ezh2 double mutant mice the acquisition of FLT3 internal tandem duplications (ITD) activating mutations (a frequent event in ETP-ALL) led to leukemia development. […] These data do not only reflect the high and complex genetic heterogeneity of this leukemic subtype but also reinforce the open debate about the cell type in which the leukemic transformation begins.

• #15

  https://omim.org/entry/613065

  Lesions in the PAX5 (167414) and IKZF1 (602023) genes, encoding B-lymphoid transcription factors, occur in over 80% of cases of pre-B-cell ALL. By combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, Chan et al. (2017) identified a novel B-lymphoid program for transcriptional repression of glucose and energy supply. The metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK (see 602739). Dominant-negative mutants of PAX5 and IKZF1 however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a nonpermissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (138040), encoding the glucocorticoid receptor, TXNIP (605051), encoding a glucose feedback sensor, and CNR2 (605051), encoding a cannabinoid receptor, as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukemic transformation. Conversely, pharmacologic TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2, and AMPK as potential therapeutic targets. Furthermore, these results provided a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.

• #15

  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.

• #16

  https://www.jci.org/articles/view/61203

  In the last five years, genome-wide profiling using microarrays, candidate gene, and second-generation sequencing have provided a number of key insights into the genetic basis of ALL. These studies have identified new subtypes of ALL and have uncovered recurring submicroscopic genetic alterations in known ALL subtypes. These include loss-of-function mutations involving genes regulating lymphoid development that contribute to the arrest in maturation characteristic of B-ALL, mutations that inactivate tumor suppressor and cell cycle regulatory proteins, and mutations that drive cytokine receptor and/or kinase signaling. Thus, as in AML, concomitant lesions disrupting hematopoietic development and tumor suppression as well as driving signaling and proliferation are hallmarks of many ALL subtypes. Importantly, several of these alterations are associated with specific subtypes of ALL defined by recurring chromosomal alterations.

• #17 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.

• #18 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.

• #19 Pathophysiology of Acute Lymphoblastic Leukemia | IntechOpen

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

  The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have shown the chromosomal rearrangements. […] 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.

• #19 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.

• #20 Childhood Acute Lymphoblastic Leukemia – NCI

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

  Childhood acute lymphoblastic leukemia (also called ALL or acute lymphocytic leukemia) is a cancer of the blood and bone marrow. ALL occurs because too many stem cells become lymphoblasts that do not mature into B lymphocytes or T lymphocytes. These cells are also called leukemia cells. Leukemia cells are not able to fight infection very well. Also, as the number of leukemia cells increases in the blood and bone marrow, there is less room for healthy red blood cells, platelets, and white blood cells. This may lead to anemia, easy bleeding, and infection. […] Childhood ALL is caused by changes to how the blood stem cells function, especially how they grow and divide into new cells. The exact cause of these cell changes is often unknown. […] 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.

• #20 Childhood Acute Lymphoblastic Leukemia – NCI

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

  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. […] For leukemia that comes back after treatment, your child’s prognosis depends partly on: how long it is between the time of diagnosis and when the leukemia comes back, whether the leukemia comes back in the bone marrow or in other parts of the body, your child’s age at relapse, your child’s risk group at initial diagnosis, your child’s initial response to treatment for the relapsed leukemia, whether the leukemia cells began from B lymphocytes or T lymphocytes, whether there are certain changes in the chromosomes or genes in the leukemia cells.

• #21 Leukaemia – Pathophysiology – Management – TeachMePaediatrics

  https://teachmepaediatrics.com/haemonc/haematology/acute-lymphoblastic-leukaemia/

  As with many malignancies, the precise aetiology of childhood leukaemia remains unknown. It is clearly a multi-factorial condition, with infection, genetic predisposition and numerous environmental exposures all playing a potential role in its development. […] Disruptions in the regulation and proliferation of lymphoid precursor cells in the bone marrow leads to excessive production of immature blast cells and a subsequent drop in numbers of functional red blood cells, white blood cells and platelets. […] Children with certain genetic diagnoses, such as trisomy 21, are known to be at increased risk of leukaemia.

• #22 Acute lymphocytic leukemia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/symptoms-causes/syc-20369077

  Acute lymphocytic leukemia occurs when a bone marrow cell develops changes (mutations) in its genetic material or DNA. A cell’s DNA contains the instructions that tell a cell what to do. Normally, the DNA tells the cell to grow at a set rate and to die at a set time. In acute lymphocytic leukemia, the mutations tell the bone marrow cell to continue growing and dividing. […] When this happens, blood cell production becomes out of control. The bone marrow produces immature cells that develop into leukemic white blood cells called lymphoblasts. These abnormal cells are unable to function properly, and they can build up and crowd out healthy cells. […] It’s not clear what causes the DNA mutations that can lead to acute lymphocytic leukemia.

• #23 Magiran | Pathogenesis of Acute Lymphoblastic Leukemia

  https://www.magiran.com/paper/2041918/pathogenesis-of-acute-lymphoblastic-leukemia?lang=en

  Acute lymphoblastic leukemia (ALL) is a hematological malignant disease characterized by an enhanced self-renewal ability of precursor lymphoid cells whose cell division takes more time than their normal counterparts. […] About 90% of ALL cases do not have a clear etiological mechanism. Genetic syndromes, polymorphic variants genes, germline mutations, and some environmental factors are responsible for less than 10% of ALL predisposition but the pathogenesis mechanism of ALL is not identified precisely. […] Here we review the recent findings and earlier studies about the pathogenesis of acute lymphoblastic leukemia and its incidence. This article also summarizes the identification of predictive factors for ALL and options available to predict disease recurrence.

• #24 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. […] In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. […] We also discuss how various elements of the bone marrow niche affect ALL chemo- and immunotherapy and present recently discovered treatment strategies that restore or stimulate the immune response to ALL. […] The impairment of the numbers and function of effector immune cells (NK cells, T cells, and M1 macrophages) may diminish the efficacy of therapeutic modalities relying on the function of these effector cells.

• #24 Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

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

  Although some recent studies showed the occurrence of ALL neoantigen-specific T cells, further research is needed to elucidate if their numbers and activity is sufficient to employ strategies aimed at restoring T cell function with immune checkpoint blockade. […] Studies explaining the mechanisms of ALL T cells’ dysfunction may also contribute to improvements in CAR-based adoptive immunotherapy.

• #25

  https://www.haematologica.org/article/view/8026

  Central nervous system (CNS) infiltration is rarely detected at initial diagnosis of pediatric acute lymphoblastic leukemia (ALL). […] This suggests that ALL cells that are refractory to therapy or particularly receptive to microenvironment-derived protective signals are able to survive in the CNS niche for prolonged periods of time as extramedullary minimal residual disease. In order to solve the mechanistic problem of CNS disease in ALL, factors influencing the homing and the survival of leukemic cells in this protective sanctuary are increasingly being investigated. […] They further investigated the role of the homeobox gene PBX1, one of the genes up-regulated in the CNS by using BCP-ALL cell lines in a co-culture model of the blood brain barrier (BBB) and in xenografts. […] Targeting PBX1 by RNA interference decreased the protective effects induced in this co-culture model pointing at a role of PBX1 as a niche-specific survival factor.

• #25

  https://www.haematologica.org/article/view/8026

  PBX1 is known to support long-term self-renewal abilities in hematopoietic stem cells and, as a translocation partner for E2A in t(1;19) positive BCP-ALL, it leads to an arrest of B cells at the pro-/pre-B-stage and is also able to enhance self-renewal capacity in pre-leukemic B-cell progenitors. […] Interestingly, E2A-PBX1 rearranged BCP-ALL has a particular propensity to enter the CNS. […] The E2A-PBX1 transgene caused the acquisition of a number of secondary activating mutations, most notably in the JAK/STAT and RAS pathways, suggesting that E2A-PBX1 induces genomic instability. […] Whether CNS leukemogenesis by PBX1 without the E2A-PBX1 rearrangement is based on similar molecular mechanisms remains to be investigated. […] It has recently been suggested that CNS infiltration is a universal feature of leukemic blasts based on pre-clinical experimental data.

• #25

  https://www.haematologica.org/article/view/8026

  On the other hand, it is also possible that only ALL cells expressing specific homing markers can enter the CNS compartment and that they activate pro-survival signaling in that niche in a second step. […] Taken together this work provides important insights into the biology of CNS infiltration in ALL which is important in the context of the previous findings on CNS leukemia of the past few years. PBX1 is established as a novel mechanism of survival and chemotherapy resistance for ALL in the CNS compartment independent of the E2A-PBX1 translocation but with important implications for this entity.

• #26

  https://link.springer.com/article/10.1007/s11899-024-00735-w

  Glucocorticoids have been an integral and mainstay component of chemotherapy regimens in ALL for decades and poor initial response to GCs is a predictor for treatment failure. The mechanisms involved in the efficacy of GCs include multiple biological pathways mediated by the interaction of the GCs and their glucocorticoid receptor (GCR) which can act as a transcriptional activator or repressor. This is achieved through direct binding to DNA or interaction with transcription factors resulting in the ability to induce cell cycle arrest, inhibit cell growth, and mediate apoptotic pathways that ultimately lead to cellular death. […] The considerable link between primary GC resistance and poor prognosis and outcomes in ALL underscores the significance of GC therapy. Poor prednisone response is defined as the presence of 1.0 10^9 blasts/L in the peripheral blood on day eight of therapy and predicts significantly higher risk for relapse and worse outcomes and as such, GC resistance identifies a high-risk population with ALL that could benefit from intensifying therapy or an alternative consolidative approach.

• #26

  https://link.springer.com/article/10.1007/s11899-024-00735-w

  Notably, the precise mechanisms of this resistance have yet to be fully understood. It is postulated that GC treatment may incur selection pressure on leukemic cells leading to acquired genetic changes that weaken a functional steroid response, leading to therapy failure and relapse. Another avenue could be subclones with mutations responsible for GC resistance being already present at the time of diagnosis such that the elimination of GC-sensitive cells causes the resistant subpopulation to become a dominant clone. […] What is evident is that the GCR plays a significant role in this process. The human GCR is a protein encoded by the NR3C1 gene comprised of 9 exons. It is widely expressed and binds GC hormones to mediate cellular and tissue-specific effects in development, metabolism, and immune response. As a result of alternate splicing of exon 9, GCR and GCR variants are produced, the latter of which is unable to bind GC. It is such that the GCR isoform is thought to contribute to GC resistance in ALL treatment by competing with GCR at the DNA-binding site and this resistance can be produced by its antagonism towards GCR. Other GCR splice variants including GCR were discovered to change GCR sensitivity and GCR expression has been linked to resistance to dexamethasone treatment in ALL. Other reported mechanisms involving the receptor include lower overall NR3C1 gene expression which leads to decreased GCR expression and has been linked to poor prognosis and tumor development.

• #26

  https://link.springer.com/article/10.1007/s11899-024-00735-w

  Through studies utilizing ALL cell lines in vitro and retrospectively evaluating clinical responses, multiple signaling pathways have been implicated in GC resistance during ALL treatment and directly correlated with GC sensitivity. The BCL-2 protein family has been identified as a critical mediator of GC-induced apoptosis and proteasomal degradation of the GCR has also been implicated in resistance to GC treatment. GC resistance has been linked to IKZF1 mutations, which are especially prevalent in Ph-like ALL. In a study of 646 pre-B ALL patients, IKZF1-deletions correlated with day 8 prednisone response and were more prevalent in poor prednisone response patients. Activation of the IL-7 signaling pathway plays a crucial role in T- and B-cell development and has been associated with T-ALL resistance to GC treatment. Activation of the PI3K/AKT/mTOR signaling cascade prevents the GCR from translocation to the nucleus and it is the activation of AKT1 that may play a role in the development of GC resistance in ALL. The MAPK-ERK pathway which takes part in controlling cellular growth and survival has also been implicated, and this is supported by enhancement of GC sensitivity when GC resistant cell lines were treated with a MAPK inhibitor.

• #26

  https://link.springer.com/article/10.1007/s11899-024-00735-w

  As discussed, steroid resistance in and of itself has been shown to confer poor prognosis and outcomes in ALL and future directions of ALL therapy could perhaps concentrate on intensifying and enhancing GC efficacy and overcoming resistance by targeting specific players in the GC/GCR signaling pathways shown to be vital in this respect. As just one example, the BCL-2 protein family has been identified as a critical mediator of GC-induced apoptosis and proteasomal degradation of the GCR has also been implicated in resistance to GC treatment.

• #27 Acute Lymphoblastic Leukemia Treatment – NCI

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

  Acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). […] ALL is caused by certain changes to the way blood stem cells function, especially how they grow and divide into new cells. A risk factor is anything that increases the chance of getting a disease. Some risk factors for cancer, like smoking, can be changed. However, risk factors also include things people cannot change, like their genetics, getting older, and their health history. […] In ALL, too many stem cells become lymphoblasts, B lymphocytes, or T lymphocytes. These cells are also called leukemia cells. Leukemia cells are not able to fight infection very well. Also, as the number of leukemia cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding. The cancer can also spread to the central nervous system (brain and spinal cord), lymph nodes, spleen, liver, testicles, and other organs.

• #27 Acute Lymphoblastic Leukemia Treatment – NCI

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

  Certain factors affect prognosis (chance of recovery) and treatment options. […] The prognosis and treatment options for ALL depend on: the person’s age, whether the cancer has spread to the brain or spinal cord, whether there are certain changes in the genes, including the Philadelphia chromosome, whether the cancer has been treated before or has recurred (come back).

• #28 Scientists discover a unique mechanism for a high-risk leukemia – St. Jude Children’s Research Hospital

  https://www.stjude.org/media-resources/news-releases/2016-medicine-science-news/scientists-discover-a-unique-mechanism-for-a-high-risk-leukemia.html

  The researchers expect that these trials will commence in the near future, because drugs that inhibit the over-activated biological pathway in the leukemia already exist and are widely used to treat other cancers. […] These findings drive home the point that we are dealing with a complex genomic landscape. […] Each one of these rearrangements is potentially its own entity, and each one merits its own detailed study. […] Such sequencing is also critical for definitive diagnosis of the cancers. […] But to fully understand these tumors, you have to look at large numbers to make correlations; and to really understand the driving mechanism, you have to find the recurrent biological changes in the tumors.

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

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

  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. Risk factors of BALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. […] Understanding the mechanisms of BALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.

• #30

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

  This concise review focuses on the most recent advances in understanding molecular genetic abnormalities in childhood acute leukemia (ALL). An increasing number of chromosomal translocations associated to distinct molecular genetic abnormalities have been described. Recurrent motifs have been recognized behind the great heterogeneity of genes involved in chromosomal translocations occurring in childhood ALL. The expression or activation of specific genes encoding for transcription factors have been recognized to be the most frequent recurring mechanism. […] In addition to the identification of genes involved in translocations, the analysis of deleted or mutated genes has provided new insights into the molecular pathogenesis of childhood ALL. The understanding of the genetic heterogeneity has turned out to have great impact on routine diagnosis and treatment. Molecular analysis has revealed that the t(12;21) translocation, barely detectable when searched for by conventional cytogenetic techniques, is the most frequent genetic lesion occurring in childhood ALL. Accumulating evidence clearly indicates that molecular characterisation at diagnosis represents the most relevant prognostic information for risk stratification of the patients at diagnosis. Several target genes are now available for the study of minimal residual disease and to evaluate its potential impact for tailoring treatment. 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.

Zobacz więcej