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Miaofen G Hu has completed his PhD from Boston University School of Medicine and postdoctoral studies from Harvard University School of Medicine. She has been Assistant Professor at TUFTS medical Center since 2011. She has published 24 papers in reputed journals. Her most significant research accomplishments thus far include creating a CDK6 mouse model, discovering the role of CDK6 as a common mediator of Notch1 and AKT1 signaling pathways, establishing the potential therapeutic role of CDK6 in T cell malignance, revealing the function of CDK6 kinase activity in negatively regulating the conversion of fat-storing cells into fat-burning cells.
Despite recent advances in chemotherapy, relapse is frequent, possibly because the available therapies do not eradicate the cells that initiate and sustain the disease in vivo, so-called leukemia stem cells (LSCs). Cyclin-dependent kinase 6 (CDK6) regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cells and over-expressed in human T-ALL/LBL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in Cdk6. These “knock-in” alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical inhibition of CDK6, respectively. We have found that CDK6 is required for initiation and maintenance of T-ALL leukemia and lymphomagenesis induced by constitutively active Notch/Myr-AKT. Pharmacologic inhibition of CDK6 kinase induces CD25 expression, cell cycle arrest, and apoptosis in mouse and human T-ALL. Ablation of Cd25 in a K43M background restores Notch-induced T-leukemogenesis, with disease that is resistant to CDK6 inhibitors in vivo. Moreover, loss of Cd25 in a K43M background restore the ability of LSCs to self-renew. These data support a model whereby CDK6-mediated suppression of CD25 is required for initiation of T-ALL by activated Notch1, and CD25 induction mediates the therapeutic response to CDK6 inhibition in established T-ALL. These results both validate CDK6 as a molecular target for therapy of this subset of T-ALL and suggest that CD25 expression could serve as a biomarker for responsiveness of T-ALL to CDK4/6 inhibitor therapy.