Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PU.1 is an Ets family transcription factor that is required for the development of myeloid and lymphoid cells. Since PU.1 is required for several different lineages it has been unclear what role PU.1 has in deciding whether a hematopoietic progenitor cell differentiates into a macrophage, granulocyte, or B cell. Recent studies have demonstrated that different cellular concentrations of PU.1 may direct distinct cell fates, with the highest concentrations of PU.1 required for macrophage development and lower concentrations for granulocytic and B-cell fate adoption. Since PU.1 transactivation activity is inhibited by the granulocytic factor, C/EBPalpha and the B-cell factor BSAP, high concentrations of PU.1 may be required for macrophage development in order to overcome the negative effects of alternative lineage specific factors. Lastly, PU.1 upregulation is implicated in the maturation of myeloid cells once they have committed to the macrophage and granulocytic lineages. PU.1 activity is inhibited in some cases of acute myelogenous leukemia (AML), therefore, inhibition of PU.1 induced maturation may be a critical step in leukemogenesis.
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PMID:The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. 1297 30

In leukemias chromosomal aberrations, balanced translocations in particular, play a critical role in the oncogenic process. The characterization of these chromosomal alterations was crucial to the discovery of the genes implicated in leukemogenesis, as the chromosomal breakpoints indicated their genomic localization. In addition, these molecular defects may serve as targets for diagnostic essays and can have a major prognostic value. Finally, the characterization of the deregulated cellular pathways potentially identifies targets for therapeutic intervention. In this paper we summarize our efforts to expand the current knowledge of the diagnostic, prognostic or biological significance of selected chromosomal aberrations identified in M-FISH studies. First, we illustrated the power of M-FISH in dissecting complex chromosomal aberrations in myeloid neoplasms. MLL amplification was defined as a clinical entity characterized by adverse prognosis and within the multitude and variety of chromosomal rearrangements a pattern of a limited number of cytogenetic subclasses was discerned. In leukemias characterized by 11q23 amplification, we described the amplicon and confirmed MLL, in addition to DDX6, as a principal amplification target. Molecular characterization of a large series of unselected sporadic and recurrent 3q26 rearranged leukemias confirmed the decisive role of ectopic EVI1 expression in these malignancies. We contributed to an extensive analysis of the phenotypical and prognostic features of T-ALL characterized by HOX11L2 expression and identified HOX11L2 overexpression as one of the most frequent genetic defects in childhood T-ALL, associated with intermediate prognosis. Finally, we designed and validated diagnostic tools for the detection of the t(9;14) (p13;q34) resulting in PAX5 overexpression and convincingly associated the presence of this rearrangement to high-grade morphology and karyotype complexity. In conclusion, the series of investigations presented here clearly illustrate the benefits of M-FISH as molecular tool for the dissection and characterization of complex and cryptic rearrangements. The subsequent reports demonstrate the utility of molecular cytogenetics and expression analyses to the clinical management of patients diagnosed with hematological malignancies.
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PMID:Acquired chromosomal rearrangements targeting selected transcription factors: contribution of molecular cytogenetic and expression analyses to the identification of clinically and biologically relevant subgroups in hematological malignancies. 1742 74

High-resolution single nucleotide polymorphism genomic microarray (SNP-chip) is a useful tool to define gene dosage levels over the whole genome, allowing precise detection of deletions and duplications/amplifications of chromosomes in cancer cells. We found that this new technology can also identify breakpoints of chromosomes involved in unbalanced translocations, leading to identification of fusion genes. Using this technique, we found that the PAX5 gene was rearranged to a variety of partner genes including ETV6, FOXP1, AUTS2, and C20orf112 in pediatric acute lymphoblastic leukemia (ALL). The 3' end of the PAX5 gene was replaced by the partner gene. The PAX5 fusion products bound to PAX5 recognition sequences as strongly as wild-type PAX5 and suppressed its transcriptional activity in a dominant-negative fashion. In human B cell leukemia cells, binding of wild-type PAX5 to a regulatory region of BLK, one of the direct downstream target genes of PAX5, was diminished by expression of the PAX5-fusion protein, leading to repression of BLK. Expression of PAX5-fusion genes in murine bone marrow cells blocked development of mature B cells. PAX5-fusion proteins may contribute to leukemogenesis by blocking differentiation of hematopoietic cells into mature B cells. SNP-chip is a powerful tool to identify fusion genes in human cancers.
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PMID:Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. 1869 40

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.
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PMID:Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. 1934 9

Copy number losses in chromosome arm 9p are well-known aberrations in malignancies, including leukemias. The CDKN2A gene is suggested to play a key role in these aberrations. In this study overviewing 9p losses in hematologic neoplasias, we introduce the term focal 9p instability to indicate multiple areas of copy number loss or homozygous loss within a larger heterozygous one in 9p. We have used microarray comparative genomic hybridization to study patients with acute lymphoblastic leukemia (ALL, n = 140), acute myeloid leukemia (n = 50), chronic lymphocytic leukemia (n = 20), and myelodysplastic syndromes (n = 37). Our results show that 9p instability is restricted to ALL. In total, 58/140 (41%) patients with ALL had a loss in 9p. The 9p instability was detected in 19% of the patients with ALL and always included homozygous loss of CDKN2A along with loss of CDKN2B. Other possibly important genes included MTAP, IFN, MLLT3, JAK2, PTPLAD2, and PAX5. 13/27 (48%) patients with the instability had the BCR/ABL1 fusion gene or other oncogene-activating translocation or structural aberrations. Two patients had homozygous loss of hsa-mir -31, a microRNA known to regulate IKZF1. IKZF1 deletion at 7p12.1 was seen in 10 (37%) patients with the 9p instability. These findings suggest that, in ALL leukemogenesis, loss of CDKN2A and other target genes in the instability region is frequently associated with BCR/ABL1 and IKZF1 dysfunction. The multiple mechanisms leading to 9p instability including physical or epigenetic loss of the target genes, loss of the microRNA cluster, and the role of FRA9G fragile site are discussed.
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PMID:Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single-nucleotide polymorphism microarray analyses. 2001 97

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
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PMID:Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study. 2016 Jan 64

PAX5 is a transcription factor required for B-cell development and maintenance. PML is a tumor suppressor and a pro-apoptotic factor. A fusion gene, PAX5-PML, was found in acute lymphoblastic leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24), but no functional analysis has been reported. Here, we demonstrate that PAX5-PML had a dominant-negative effect on both PAX5 and PML. PAX5-PML dominant negatively inhibited PAX5 transcriptional activity in the luciferase reporter assay and suppressed the expression of the PAX5 transcriptional targets in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA-binding activity in vitro although it retained the DNA-binding domain of PAX5. Additional experiments, including chromatin immunoprecipitation (ChIP) assay, suggested that PAX5-PML bound to the promoter through the association with PAX5 on the promoter. On the other hand, coexpression of PAX5-PML inhibited PML sumoylation, disrupted PML nuclear bodies (NBs), and conferred apoptosis resistance on HeLa cells. Furthermore, treatment with arsenic trioxide (ATO) induced PML sumoylation and reconstitution of PML NBs, and overcame the anti-apoptotic effect of PAX5-PML in HeLa cells. These data suggest the possible involvement of this fusion protein in the leukemogenesis of B-ALL in a dual dominant-negative manner and the possibility that ALL with PAX5-PML can be treated with ATO.
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PMID:PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. 2121 75

The PAX5 is essential in normal B-cell lymphopoiesis and deregulation of PAX5 function is believed to contribute to leukemogenesis in B-ALL. We performed a comprehensive study using FISH, G-banding and IHC to identify PAX5 deletion and expression in 102 CD19+ clinical B-ALL cases (79 children and 33 adults) and investigated its relationship with common cytogenetic changes including BCR-ABL1, ETV6-RUNX1 and MLL rearrangements, and CDKN2A deletion. The incidences of translocations and deletions were 2.5% and 10.0% in children, and 0.0% and 18.2% in adults, respectively. The incidence of PAX5 deletion was higher than those of BCR-ABL1 (8.9%) or MLL rearrangements (5.1%) in children and than that of MLL rearrangement (3.1%) in adults. Most patients with PAX5 deletion (83.3% of children and 100.0% of adults with PAX5 deletion) had concurrent CDKN2A deletion. PAX5 deletions were detected both in patients with positive and negative PAX5 expression. In this study, we found that PAX5 is a common target in leukemogenesis of B-ALL along with CDKN2A. Owing to its frequent deletion in B-ALL, PAX5 could be used as one of the molecular markers in diagnosis and monitoring of the disease. No correlation between expression of PAX5 and deletion of PAX5 suggests allele-specific regulation.
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PMID:PAX5 deletion is common and concurrently occurs with CDKN2A deletion in B-lineage acute lymphoblastic leukemia. 2154 23

The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.
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PMID:BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. 2402 25

Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.
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PMID:Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia. 2493 36


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