Deregulation of HOX genes by DNMT3A and MLL mutations converges on BMI1

Yt, Tan; Sun, Yang; Zhu, Shuijin; L, Ye; Cj, Zhao; Wl, Zhao; Chen, Z; Sj, Chen; Liu, Han

doi:10.1038/leu.2016.15

Cited by 9 publications

(5 citation statements)

References 15 publications

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“…We then examined the relationship between the DNMT3A mutations and DNA methylation levels at PcG target developmental genes in AML. Consistent with the assumption that DNMT3A-inactivating mutations impair repression of PcG target developmental genes, previous studies reported that some PcG target developmental genes, such as HOX genes and MEIS1, are dysregulated in AML and Dnmt3a null mouse hematopoietic stem cells [28][29][30] . To explore this further, we examined a correlation between the presence of the DNMT3A mutations and DNA methylation levels at PcG target developmental genes in AML using public datasets (GSE62298).…”

Section: Dna Hypomethylated Escs For De Novo Methylation Analysissupporting

confidence: 56%

Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

et al. 2020

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De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

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Section: Dna Hypomethylated Escs For De Novo Methylation Analysissupporting

confidence: 56%

Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

et al. 2020

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“…By deciphering clonal architecture, Tan et al showed that KMT2A-PTD was not a driver mutation and usually arises after IDH2/1, DNMT3A, U2AF1 or TET2 mutations. Interestingly, proliferative mutations such as FLT3-ITD or RAS mutations seemed to appear later and were largely subclonal [ 19 ]. These clinical observations are in line with the previously reported KMT2A-PTD mice model.…”

Section: Discussionmentioning

confidence: 99%

Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication

Antherieu

Bidet

Huet

et al. 2021

Cancers

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Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients.

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“…As a consequence, at least in the first two genes, hypomethylation on HOXA alleles, and resultant HOXA hyperexpression occurs. [ 40 - 42 ] By contrast, good risk CBF +ve AMLs, which display highly durable induction/consolidation chemotherapy outcomes, display severe HOXA/B hypoexpression within bulk and CD34+ cells, in association with leukemic stem cell content of limited depth. [ 24 , 29 ] Thus, modulation of chemosensitivity may require diminution of the chemoresistance effector and LSC driving factor HOXA9 .…”

Section: Discussionmentioning

confidence: 99%

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML

et al. 2017

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Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML’s, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

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Deregulation of HOX genes by DNMT3A and MLL mutations converges on BMI1

Cited by 9 publications

References 15 publications

Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML

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