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. ? ?
| 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 |
