DNMT3A mutants provide proliferating advantage with augmentation of self-renewal activity in the pathogenesis of AML in KMT2A-PTD-positive leukemic cells

Bera, Rabindranath; Chiu, Ming-Chun; Huang, Ying‐Jung; Huang, Gang; Lee, Yun‐Shien; Shih, Lee‐Yung

doi:10.1038/s41389-020-0191-6

Cited by 11 publications

(11 citation statements)

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“…A recent study linked high initial KMT2A -PTD RNA levels to poor disease outcomes, however other studies have reported conflicting results [5,35,36]. KASUMI6, derived from a relapsed AML with a dominant negative CEBPA mutation, may provide a useful model to better understand pathogenicity of KMT2A -PTD complexity, whereas many KMT2A -PTD studies have relied on EOL1, which harbors a simple KMT2A -PTD and was derived from a chronic eosinophilic leukemia with a FIP1L1-PDGFRA fusion [6,37].…”

Section: Discussionmentioning

confidence: 99%

Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes

et al. 2021

Preprint

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KMT2A partial tandem duplication (KMT2A-PTD) at 11q23.3 is associated with adverse risk in AML and MDS, is a potential therapeutic target, and is an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. While it has been reported that KMT2A-PTD affects only a single allele, it has been theorized but not proven that duplications or genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. Copy neutral loss of heterozygosity (CN-LOH) of 11q has also been described and is known to be associated with mutations in CBL but has not been reported to involve KMT2A-PTD. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including CN-LOH and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML versus MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.

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Section: Discussionmentioning

confidence: 99%

Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes

et al. 2021

Preprint

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“…For DNMT3A, a prevailing tumor suppressor function was described [20][21][22] , making a dependency function unlikely. Amid complexity, a tumor-supportive function of mutant DNMT3A was reported in specific AML subsets, e.g., AML driven by a partial tandem duplication in KMT2A 24 . AML-388 harbors a KMT2A-AFDN translocation (Table S2),…”

Section: To the Editormentioning

confidence: 99%

WT1 and DNMT3A play essential roles in the growth of certain patient AML cells in mice

Ghalandary

Gao

Amend

et al. 2023

Blood

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Conflict of interest: COI declared -see noteCOI notes: M.M. is a former employee at AstraZeneca, academically collaborates with AstraZeneca, GSK and Roche, and receives funding from GSK and Roche. Preprint server: No; Author contributions and disclosures: M.G. designed all experiments, performed PDX experiments and designed figures; Y.G. performed certain PDX experiments, all cell line experiments and designed figures; D.A. performed CLUE cloning; G.K. and M.M. analysed DepMap data; B.V. established PDX models and in vivo chemotherapy protocols; K.S. provided primary AML samples; M.R.T. and K.H.M. performed panel sequencing; E.B. and V.J. analysed the scrb seq data; and I.J. designed the study, guided the experiments and wrote the manuscript, with the help of all authors. Non-author contributions and disclosures: No;Agreement to Share Publication-Related Data and Data Sharing Statement: Transcriptome data generated in this study are publicly available in Gene Expression Omnibus (GEO) at (XXX ID will be provided before publication). Proteome data generated in this study are publicly available in Proteomics Identification Database (PRIDE) at (XXX ID will be provided before publication). Whole Exome Sequencing raw data generated in this study are not publicly available due to information that could compromise patient privacy or consent but are available upon reasonable request from the corresponding author. Clinical trial registration information (if any):

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“…Partial tandem duplication of KMT2A (KMT2A-PTD), also named MLL-PTD, is a common genomic aberration in AML. 6 Although many studies have evaluated the prognostic effect of KMT2A-PTD in patients with AML, the results among these studies are still inconsistent. Some studies reported that KMT2A-PTD had a worse prognostic impact on patients with AML, [7][8][9][10] whereas others showed no additional prognostic impact of KMT2A-PTD.…”

Section: Strengths and Limitations Of This Studymentioning

confidence: 99%

“…We used the NOS to evaluate the quality of the 17 cohort studies. The mean score of the 17 included cohort studies was 7.65 (5)(6)(7)(8), indicating that the 17 included studies were of high quality. One study was a phase 3 randomised controlled trial, which was considered to be high quality (online supplemental table 1).…”

Section: Quality Assessment Of the Included Studiesmentioning

confidence: 99%

“…These fragments are recombined and further assembled into different multiprotein complexes to regulate the transcription of specific target genes containing many HOX genes (provided by RefSeq, October 2010). Partial tandem duplication of KMT2A ( KMT2A -PTD), also named MLL -PTD, is a common genomic aberration in AML 6. Although many studies have evaluated the prognostic effect of KMT2A -PTD in patients with AML, the results among these studies are still inconsistent.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance ofKMT2A-PTD in patients with acute myeloid leukaemia: a systematic review and meta-analysis

et al. 2023

BMJ Open

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ObjectivesWhetherKMT2A-PTD has a prognostic impact on patients with acute myeloid leukaemia (AML) is controversial. Therefore, we conducted a meta-analysis to assess the prognostic value ofKMT2A-PTD in patients with AML.MethodsEligibility criteria: we included studies concerning the prognostic value ofKMT2A-PTD in patients with AML.Information sources: Eligible studies were identified from PubMed, Embase, Medline, Web of Science, Cochrane Library and Chinese Biomedical Database. The systematic search date was 19 December 2020.Risk of bias: Sensitivity analysis was used to evaluate the stability and reliability of the combined results. Begg’s and Egger’s tests were used to assess the publication biases of studies.Synthesis of results: We calculated the pooled HRs and their 95% CIs for overall survival (OS) and event-free survival (EFS) by Stata V.12 software.ResultsIncluded studies: 18 studies covering 6499 patients were included.Synthesis of results:KMT2A-PTD conferred shorter OS in total population (HR=1.30, 95% CI 1.09 to 1.51). In the subgroup analysis,KMT2A-PTD also resulted in shorter OS in karyotypically normal AML patients (HR=2.72, 95% CI 1.83 to 3.61) and old AML patients (HR=1.93, 95% CI 1.44 to 2.42).KMT2A-PTD indicated no prognostic impact on EFS in total population (HR=1.26, 95% CI 0.86 to 1.66). However, in the sensitivity analysis,KMT2A-PTD resulted in poor EFS (HR=1.34, 95% CI 1.04 to 1.64) when deleting the study with a relatively obvious effect on the combined HR. In the subgroup analysis,KMT2A-PTD was associated with poor EFS in old AML patients (HR=1.64, 95% CI 1.25 to 2.03).ConclusionThe findings indicated thatKMT2A-PTD had an adverse impact on the prognosis of patients with AML in the total population, and the conclusion can also be applied to some subgroups including karyotypically normal AML and old AML patients.KMT2A-PTD may be a promising genetic biomarker in patients with AML in the future.Trial registration numberCRD42021227185.

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DNMT3A mutants provide proliferating advantage with augmentation of self-renewal activity in the pathogenesis of AML in KMT2A-PTD-positive leukemic cells

Cited by 11 publications

References 45 publications

Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes

WT1 and DNMT3A play essential roles in the growth of certain patient AML cells in mice

Prognostic significance ofKMT2A-PTD in patients with acute myeloid leukaemia: a systematic review and meta-analysis

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