The objectives of this proposal are to understand the molecular and cellular pathways that cooperate with inv(16), one of the most common chromosomal mutations found in human acute myeloid leukemia (AML). Inv(16) creates a fusion gene CBFB-MYH11, which predisposes mice to AML but is not sufficient to trigger leukemogenesis. One of the candidate Cbfb-MYH 11 cooperating genes, Runx2, will be functionally characterized in hematopoiesis and AML. To further identify Cbfb-MYH1 1 cooperating genes, retrovirus insertional mutagenesis screen in conditional Cbfb-MYH 11 knock-in BXH-2 mouse model will be carried out. Furthermore, functional characterization of the identified candidate genes will be accomplished by reconstitution experiments in vivo in parallel to in vitro proliferation and apoptosis analyses. Through these studies, we will make major progress in revealing the molecular mechanisms in regulating homeostasis of hematopoietic stem cells. Moreover, the elucidation of novel pathways and the molecular mechanisms implicated in inv(16) associated AML development will directly benefit the understanding of AML formation in humans and shed light on the development of novel therapeutic approaches. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA101571-03
Application #
7090077
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$52,048
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Kuo, Ya-Huei; Zaidi, Sayyed K; Gornostaeva, Svetlana et al. (2009) Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood 113:3323-32
Kuo, Ya-Huei; Gerstein, Rachel M; Castilla, Lucio H (2008) Cbfbeta-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development. Blood 111:1543-51
Kuo, Ya-Huei; Landrette, Sean F; Heilman, Susan A et al. (2006) Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell 9:57-68
Heilman, Susan A; Kuo, Ya-Huei; Goudswaard, Chantal S et al. (2006) Cbfbeta reduces Cbfbeta-SMMHC-associated acute myeloid leukemia in mice. Cancer Res 66:11214-8