Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

Pedersen‐Bjergaard, Jens; Christiansen, Debes H.; Andersen, M. S.; Skovby, Flemming

doi:10.1038/sj.leu.2402764

Cited by 45 publications

(23 citation statements)

References 110 publications

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“…Two main cytogenetic pathways have been proposed to explain the malignant transformation step in patients with therapy-related MDS (t-MDS): [29][30][31] pathway I is 'À7/7q-with normal chromosome 5', and pathway II is 'À5/5q-'. The patients belonging to the pathway I group frequently show mutations of RAS genes 32 and methylation of the p15 INK4b gene promoter.…”

Section: Discussionmentioning

confidence: 99%

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Niimi

Harada

et al. 2006

Leukemia

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AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/ AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with À7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of À5/5q-and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, Po0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signalregulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/ RUNX1 mutations has a significant association with À7/7q-alteration, and frequently involves RTK-RAS signaling pathway activation.

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Section: Discussionmentioning

confidence: 99%

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Niimi

Harada

et al. 2006

Leukemia

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“…RUNX1 was frequently mutated in myeloid neoplasms in atomic-bomb survivors and in patients with radiation therapyrelated myeloid neoplasms [48,49].…”

Section:  Genetic Changes Triggering Malignant Transformationmentioning

confidence: 99%

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Schlegelberger

Heller

2017

Seminars in Hematology

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In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL.Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into iPSC lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.  Definition of RUNX1 deficiency/ FPDMMRUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e. t(12;21)/RUNX1/ETV6 in pediatric acute lymphoblastic leukemia, t(8;21)/RUNX1/RUNX1T1 in acute myeloid leukemia (AML), and t(3;21)/RUNX1/EVI1 in therapy-related AML or chronic myeloid leukemia in blast phase [2,3]. Moreover, somatic RUNX1 mutations have recently been identified as recurrent abnormalities in myelodysplastic syndromes (MDS) and AML [4]. These somatic changes are associated with poor prognosis in AML and MDS indicating an increased resistance against exposure to genotoxic agents. RUNX1 mutations seem to trigger progression into MDS and AML in Fanconi anemia and severe congenital neutropenia [5,6]. Song et al. (1999) were the first to describe heterozygous germline RUNX1 mutations in six families, each carrying a different mutation. Individuals carrying germline RUNX1 may be asymptomatic throughout lifetime or develop familial platelet disorder with myeloid malignancies (i.e. FPDMM, OMIM 601399). Characteristic features are 1) mild to moderate thrombocytopenia; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. There is a great phenotypic heterogeneity. FPDMM is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.  Diagnostic criteria to identify persons at riskSince the diagnosis of FPDMM in a patient with leukemia carries important critical implications for the patient and also for her/his family, it is important to recognize clinical features pointing to this genetic predisposition [7]. An important clinical feature is persisting thrombocytopenia or aspirin-like platelet disorder, which are not explained by other reasons.Thorough pedigree analysis may identify first or second degree relatives with bleeding tendency or hematological neoplasms. It has to be kept i...

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“…19 The two most common pathways in patients treated with alkylating agents were pathway I characterized by deletion or loss of 7q but with normal chromosomes 5, and pathway II characterized by deletion or loss of 5q with or without normal chromosomes 7. Pathway II was significantly associated with deletion or loss of chromosome arm 17p and mutation of the p53 gene, with duplication or amplification of chromosome band 11q23 and with a complex karyotype.…”

Section: Tablementioning

confidence: 99%

“…18 At least eight genetic pathways of t-MDS and t-AML were recently outlined. 19 The purpose of the present study was to examine the methylation status of the p14, p15, and p16 gene promoters in 81 unselected patients with t-MDS or t-AML and to relate the results to type of previous therapy, to clinical, cytologic, and cytogenetic characteristics, as well as to the different genetic pathways of the disease.…”

Section: Introductionmentioning

confidence: 99%

Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia

2003

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The p14 ARF , p15 INK4B , and p16 INK4A genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapyrelated myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P ¼ 0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P ¼ 0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P ¼ 0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P ¼ 0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P ¼ 0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.

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Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities

Cited by 45 publications

References 110 publications

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia

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