HYPOMETHYLATING DRUGS SPECIFICALLY TARGET DNMT3A MUTATION ASSOCIATED CLONAL HEMATOPOIESIS AND ACUTE MYELOID LEUKEMIA
Author(s): ,
Marina Scheller-Wendorff
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg,Heidelberg,Germany
,
Anne Kathrin Ludwig
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg,Heidelberg,Germany
,
Christian Rohde
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg,Heidelberg,Germany
,
Sina Staeble
Affiliations:
Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors,German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Stephen Kraemer
Affiliations:
Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors,German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Nicole Bäumer
Affiliations:
Department of Medicine A, Hematology, Oncology,University Hospital Münster,Münster,Germany
,
Christian Arnold
Affiliations:
Structural and Computational Biology Unit,European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Judith Zaugg
Affiliations:
Structural and Computational Biology Unit,European Molecular Biology Laboratory (EMBL),Heidelberg,Germany
,
Daniel B. Lipka
Affiliations:
Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors,German Cancer Research Center (DKFZ),Heidelberg,Germany
Carsten Müller-Tidow
Affiliations:
Department of Medicine V, Hematology, Oncology and Rheumatology,University Hospital Heidelberg,Heidelberg,Germany
EHA Library. Scheller-Wendorff M. Jun 15, 2019; 267270; PS969
Marina Scheller-Wendorff
Marina Scheller-Wendorff
Contributions
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Abstract

Abstract: PS969

Type: Poster Pitch

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

DNMT3A mutations commonly occur in myeloid malignancies and in clonal hematopoiesis. The codon arginine 882 (R882) is the major hotspot mutation in patients with de novo AML, in secondary AML as well as in individuals with clonal hematopoiesis in the absence of leukemic transformation. Although the majority of patients with DNMT3A-R882H AML initially respond to conventional chemotherapy, many of them subsequently relapse, suggesting that DNMT3A-R882H cells persist and drive relapse. No specific therapy exists to date for clonal hematopoiesis or DNMT3A-R882H mutated AML. Recent studies have shown that DNMT inhibitors (DNMTi) could be particularly beneficial for patients with DNMT3A mutations. However, the extent of this association, the potential to cure patients and the mechanisms remain unresolved.

Aims

Our aim is to identify in which context leukemic and pre-leukemic stem cells with DNMT3A-R882 mutation can be targeted by DNMT-inhibitors as mono-therapy and in combination.

Methods

In order to understand the molecular and functional consequences of the DNMT3A-R882H mutation in leukaemogenesis we generated a novel, inducible knock-in mouse line of human DNMT3A-R882H mutations (DNMT3AR882H). DNMT3AR882H knock-in mice that harbored a floxed stop cassette upstream of the Dnmt3a gene were crossed with mice carrying an interferon-inducible Cre recombinase allele (Mx1-Cre). Upon Cre induction the endogenous mouse Dnmt3a gene from exon 2 was efficiently replaced by human DNMT3A cDNA carrying the R882H mutation.

Results

Analysis of aged DNMT3AR882H knock-in mice at pre-leukemic stage revealed accumulation of myeloid progenitor (GMP) and stem cells (HSC), which showed loss of dormancy, increased cell cycle and exhaustion in serial retransplantation in vivo. Using mouse model of leukemia by mouse-intercross and retroviral infection, we have confirmed that DNMT3AR882H mutation accelerated leukaemogenesis in the presence of FLT3-ITD, MLL-AF9 and Myc-Bcl2, whereas DNMT3AR882H mutation alone did not induce leukemia in mice up to eighteen months after Cre induction.

In search of therapeutic strategies, we identified that DNMTi specifically target DNMT3A-R882H mutant pre-leukemic HSC and leukemic blasts. Loss of DNA methylation in DNMT3A-R882H HSCs associated with enhanced immune signals including increased expression of endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. A single therapy cycle of low dose DNMTi (5-Azacytidine) treatment accelerated loss of DNA methylation in DNMT3A-R882H HSCs and exhaustion of DNMT3A-R882H mutant hematopoiesis. 5-Azacytidine in combination with chemotherapy induced long lasting remissions in DNMT3A-R882H murine leukemias.

Conclusion
These findings may open the path towards targeted therapy of DNMT3A mutated clonal hematopoiesis and AML.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): AML, Azacitidine, DNA methylation, Epigenetic

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