First name
Parinaz
Last name
Mehdipour
Year of Study
Research Center
Thesis Title
Dissecting the role of histone deacetylase 3 (HDAC3) in leukemogenesis
Thesis Abstract
Acute Promyelocytic Leukemia (APL) is the first model disease in which the
involvement of HDACs has been documented. In this study we characterized the role
of HDAC3 through a functional knock-down approach, assessing its impact on
cellular differentiation, proliferation and the ability to influence the transplantation of
HSCs and APL cells. Indeed, Hdac3-KD in vitro reduced the proliferative potential of
both pre-leukemic and full leukemic cells and boosted their differentiation, suggesting
that HDAC3 plays the role of an oncogene in APL initiation and progression. These
results were not restricted to APL, because lymphoma driven by c-myc
overexpression and leukemia driven by MLL-AF9, were both impaired in cell growth
upon Hdac3-KD. In vivo, inoculation of Hdac3-KD pre-leukemic cells into lethally
irradiated recipient mice or inoculation of Hdac3-KD APL cells into the recipient
mice did not result in leukemia development or progression, respectively. These
results suggest that HDAC3 can be considered as a target for epidrugs in the treatment
of hematological malignancies. Thus, we assessed this hypothesis with the treatment
of pre-leukemic and leukemic cells with the HDAC3 selective inhibitor, RGFP966.
Indeed, inhibition of HDAC3 enzymatic activity with RGFP966, phenocopied Hdac3-
KD phenotypes in pre-leukemic and leukemic cells confirming the putative oncogenic
role of HDAC3.
In conclusion, my PhD project has expanded our comprehension about the role of
HDAC3 in hematological malignancies and is beginning to unravel alternative views
on the targets of epidrugs for the treatment of leukemic patients.
involvement of HDACs has been documented. In this study we characterized the role
of HDAC3 through a functional knock-down approach, assessing its impact on
cellular differentiation, proliferation and the ability to influence the transplantation of
HSCs and APL cells. Indeed, Hdac3-KD in vitro reduced the proliferative potential of
both pre-leukemic and full leukemic cells and boosted their differentiation, suggesting
that HDAC3 plays the role of an oncogene in APL initiation and progression. These
results were not restricted to APL, because lymphoma driven by c-myc
overexpression and leukemia driven by MLL-AF9, were both impaired in cell growth
upon Hdac3-KD. In vivo, inoculation of Hdac3-KD pre-leukemic cells into lethally
irradiated recipient mice or inoculation of Hdac3-KD APL cells into the recipient
mice did not result in leukemia development or progression, respectively. These
results suggest that HDAC3 can be considered as a target for epidrugs in the treatment
of hematological malignancies. Thus, we assessed this hypothesis with the treatment
of pre-leukemic and leukemic cells with the HDAC3 selective inhibitor, RGFP966.
Indeed, inhibition of HDAC3 enzymatic activity with RGFP966, phenocopied Hdac3-
KD phenotypes in pre-leukemic and leukemic cells confirming the putative oncogenic
role of HDAC3.
In conclusion, my PhD project has expanded our comprehension about the role of
HDAC3 in hematological malignancies and is beginning to unravel alternative views
on the targets of epidrugs for the treatment of leukemic patients.
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