As part of a complex ensemble of hematopoietic regulators, HOXA9 helps maintain the balance between hematopoietic stem/progenitor cell (HSPC) self-renewal and myeloid/lymphoid cell differentiation in the bone marrow. Several genetic mutations observed in acute myeloid leukemia (AML) patients are associated with aberrant upregulation of HOXA9, thus disrupting the hematopoietic balance towards leukemogenesis. Altogether, HOXA9 is overexpressed in ~2/3rd of AMLs. Our preliminary data suggest a molecular interplay occurring on chromatin between HOXA9 and OGT, an O-linked N-acetyl glucosamine transferase, during HOXA9-driven leukemogenesis. In this R01 project, we propose to characterize the molecular mechanisms in which these proteins are involved to govern hematopoietic development and how disruptions of these molecular mechanisms can lead to leukemogenesis. Their impact on chromatin remodeling and their role in defining the fate of hematopoietic cells in the bone marrow will be investigated using cell-based and in vivo models of leukemogenesis. Our project should offer the means to manipulate those molecular mechanisms in leukemia patients for therapeutic benefit.

Public Health Relevance

Acute leukemia affects ~20,000 persons every year in the USA and is one of the leading causes of death in children. Successful achievement of the proposed aims will help define improved therapeutic regimens to increase survival of leukemia patients and reduce severe side-effects associated with current therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA187903-02
Application #
9119798
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Mufson, R Allan
Project Start
2015-08-15
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Xu, Tao; Park, Sung-Soo; Giaimo, Benedetto Daniele et al. (2017) RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. EMBO J 36:3232-3249