Transcriptional Targets Mediating the MYB Addiction of Ph+ Acute Lymphoblastic Leukemia
Ph+ acute lymphoblastic leukemia (ALL) is an aggressive disease characterized by a poor long-term survival due to the failure of current therapies. MYB is a transcription factor necessary for the maintenance of normal hematopoietic stem cells; however, multiple lines of evidence suggest that a partial reduction of MYB levels is tolerated by normal cells but severely affects leukemia of different types. This selective requirement for MYB by leukemia cells has potentially important therapeutic implications, but the mechanisms and factors mediating this oncogene addiction have not been fully elucidated. We investigated the requirement for MYB in mouse models, in human cell lines and in primary samples of Ph+ ALL. We found that a 50% decrease of MYB levels significantly impairs the leukemogenesis induced by p190-BCR-ABL1 in mouse models and that part of the oncogenic properties of MYB depend on the regulation of BMI1 expression. In human cells, we discovered that the proliferative and survival signals induced by MYB are primarily due to the transcriptional regulation of CDK6 and BCL2 respectively. CDK6 and MYB expression are highly correlated not only in Ph+ ALL but also in childhood Ph-negative ALL and in AML. Moreover, we show that CDK6 has a non-redundant role with CDK4 which is sequestered in the cytoplasm of Ph+ ALL cells. We found that MYB regulates CDK6 expression transcriptionally by a p300/CBP-dependent mechanism whereas p300/CBP recruitment is dispensable for MYB dependent BCL2 up-regulation. Finally, as a proof-of concept we show that the combination of the CDK4/6 inhibitor Palbociclib with the pan-BCL2 inhibitor Sabutoclax displays synergistic effects in suppressing leukemia growth in vitro and in reducing the leukemia burden in patient-derived xenografts. These results suggest that the combined inhibition of CDK6 and BCL2 may represent a potential novel therapeutic strategy for Ph+ ALL and an alternative option for patients relapsing after treatment with conventional agents. Our approach represents a rationale strategy for exploiting the oncogene addiction of cancer cells, while at the same time, overcoming the limitations due to the difficulty in pharmacologically modulating “hard-to-drug” targets such as transcription factors.
De Dominici, Marco, "Transcriptional Targets Mediating the MYB Addiction of Ph+ Acute Lymphoblastic Leukemia" (2018). ETD Collection for Thomas Jefferson University. AAI10973835.