Project Details
Projekt
Alterations of H3K9me2 in hematopoietic stem cells: implications for aging and myeloid leukemogenesis
Applicant
Professor Dr. Hartmut Geiger, since 11/2018
Subject Area
Hematology, Oncology
Term
from 2017 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 336840530
Upon aging HSCs show a critical functional decline that is paralleled by changes in global and local DNA and histone methylation as well as histone acetylation. This epigenetic drift might contribute to aberrant DNA transcription or impair DNA replication and repair, and might by this means contribute to the development of cancer. For instance, AML is predominantly a disease of older patients that originates in hematopoietic progenitor/stem cells and affects substantially the epigenome. The epigenome of leukemia stem cells (LSCs) is maintained in the myeloblast and influence aggressiveness and outcome of the disease. Recently it was shown that the histone demethylase JMJD1C functions as a coactivator for RUNX1RUNX1T1 (formerly AML1ETO) and is required for its transcriptional program in AML by maintaining low levels specifically of H3K9me2, further implying a direct connection between changes in epigenetics of HSCs and AML. H3K9me2 though has not been studied so far in HSCs and upon aging and leukemic transformation. Preliminary data from my laboratory indicate that the distribution of H3K9me2 in the nucleus of quiescent murine HSCs and in daughter cells upon murine HSC division is distinctly altered upon aging. Treatment of aged HSCs with CASIN restored a youthful distribution of H3K9me2 in aged HSCs and in daughter cells upon stem cell division.Based on my preliminary data and on data recently published by others, I hypothesize that alterations in H3K9me2 deposition upon aging of HSCs contribute to the aging-associated transition of HSCs to AML stem cells and targeting H3K9me2 distribution via CASIN treatment and/or H3K9me2 levels via inhibition of the histone demethylase JMJD1C could represent an approach to decrease aggressiveness of LSCs in AML.Therefore the current proposal aims are (1) to determine the extent of the alterations in H3K9me2 distribution/levels upon aging of murine HSCs and investigate whether the aging-associated changes are reverted to a youthful level by CASIN treatment of by inhibition of JMJD1C activity; (2) to investigate whether human HSCs present, similar to murine HSCs, with changes in H3K9me2 distribution upon aging; (3) to determine whether AML stem cells present with altered H3K9me2 distribution and investigate whether targeting the level and/or the distribution of H3K9me2 in murine LSCs alters leukemia initiation and progression.
DFG Programme
Research Units
Ehemalige Antragstellerin
Professorin Maria Carolina Florian, Ph.D., until 11/2018
