Loss of Stress Sensor GADD45a and GADD45b Accelerates BCR-ABL-Driven Leukemogenesis Via Distinct Signaling and Cellular Pathways.

Abstract 1217

The bcr/abl oncogene causes chronic myelogenous leukemia (CML) in humans. BCR/ABL is known to localize to the cytoskeleton and to display a constitutively active tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and survival. This is accomplished via several adapter proteins and signaling pathways, including Ras, PI3K-AKT, PkD2-NFkB and JAK-STAT5, all of which are believed to participate in the pathogenesis of CML. The complex nature of these signaling pathways and how they contribute to the initiation and progression of CML is only partially understood. The Gadd45 family of genes (Gadd45a, Gadd45b & Gadd45g) encode for small (18 kd) nuclear proteins that are rapidly induced by multiple stressors, including genotoxic and oncogenic stress. They are involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli through MAPK and JNK/SAPK pathways. Furthermore Gadd45a has been identified as a mediator of oncogenic Ras signaling. GADD45 proteins are upregulated during myeloid lineage terminal differentiation. To investigate if and how GADD45A and GADD45B play a role in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with wild type, gadd45a or gadd45b null myeloid progenitors transduced with a retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. It was observed that loss of gadd45a or gadd45b accelerates the development of BCR/ABL driven leukemia in wild type recipients. BCR/ABL transformed gadd45a or gadd45b deficient progenitor recipients exhibited significantly accelerated kinetics of increase in the number of WBC and percentage of myeloid blasts in blood compared to mice reconstituted with the same number of wild type bone marrow cells transduced with BCR/ABL. There was also increase in the rate of accumulation of CD11b+Gr1+ cells in the bone marrow and spleen. Using in vitro and in vivo BrdU assays, enhanced proliferation capacity was observed for BCR/ABL transduced gadd45a, but not gadd45b, deficient myeloid progenitors. However, impaired apoptosis was observed both in BCR/ABL transduced gadd45a and gadd45b deficient myeloid progenitors. These results indicate that both gadd45a and gadd45b function as suppressors of the development of BCR/ABL driven CML, where gadd45a appears to suppress CML via a mechanism involving both inhibition of cell proliferation and enhancement of apoptosis, whereas gadd45b appears to effect only apoptosis. Enhanced JNK signaling was observed in both gadd45a and gadd45b deficient progenitors, whereas enhanced p38 and AKT signaling was observed only in gadd45a deficient myeloid progenitors. Taken together, these data indicate that loss of either gadd45a or gadd45b accelerates BCR-ABL driven CML via distinct signaling and cellular pathways. Further elucidating the role Gadd45 stress sensors play in suppressing the development of leukemia should increase understanding of the molecular/cellular pathology BCR/ABL mediated leukemogenesis, and has the potential to lead to the development of new/improved modalities for treatment of leukemia.