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The Miaofen Hu laboratory is studying the role of CDK6 in Notch-mediated stem cell transformation and leukemogenesis.
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of stem cells in the bone marrow that produce white blood cells in the body that normally fight infections. Despite recent advances in therapy, relapse is inevitable because the available therapies do not properly destroy enough cancer stem cells. Recent evidence indicates that more than half of all cases of T-ALL have constitutive active Notch1 receptor and abnormalities in PTEN and AKT pathway. However, blocking the activation of Notch1 fails to inhibit some T-ALL cells. The resistance to inhibition is due to the absence of PTEN, which results in constitutive activation of AKT. Uninhibited AKT activation leads to deregulated survival and proliferation independent of Notch signaling. Therefore, to improve therapeutic efficacy in human T-ALL, it is necessary either to inhibit both pathways or seek a common downstream mediator of the Notch1 and PI3K-AKT signaling pathways. We have found that cyclin-dependent kinase 6 (CDK6) is such a common mediator.
CDK6 regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cells and over-expressed in all cases of T-LBL/ALL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in the Cdk6 gene. These knockin alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical intervention, respectively. Thus, these mouse models in hand are suitable to assess the relative contribution of Cdk6 kinase activity and non-catalytic activity to transformation and leukemogenesis. These animals therefore serve as useful tools for preclinical models of CDK6 function in cancer.
Our laboratory studies the role of CDK6 in T-cell development and Leukemogenesis, with the aim of determining and identifying the novel therapeutic target genes regulated by CDK6 in these processes.
CDK6 regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cell and over-expressed in human T-ALL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in Cdk6. These knockin alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical intervention, respectively.
We have found that Cdk6 and its kinase activity are required for proper development of thymocytes and for homeostasis of hematopoietic stem cells (HSCs), and for Notch-dependent proliferation, differentiation and survival. We have also found CDK6 is required for initiation of lymphomagenesis induced by active Myr-AKT. Thus, CDK6 may regulate leukemia and lymphoma formation and dissemination at multiple levels, and as such is an intriguing target for therapeutic intervention. Those evidence leads to the hypothesis that CDK6 has a role in Notch-mediated transformation.
By using retroviral transduction/in vivo bone marrow transplantation techniques and our refined Cdk6 mutant mice, we are able to determine which functional domains of Cdk6 is required for initiation and sustaining Notch-driven leukemogenesis, and to investigate how alterations of Cdk6 kinase activity may affect, at the molecular and cellular level, Notch signaling in stem cell transformation.
Figure 1. Notch signaling is essential for T cell lineage commitment, dvelopment, and lekemogenesis. CDK6 serves a common downstream mediator of the Notch1 and PI3K-AKT signaling pathways and may play a very important role in T-cell development and leukemogenesis.
Miaofen G. Hu, MD, PhD
XiaoLi hou, PhD
Post-doc Research Fellow
View all publications via PubMed
Note: previous name Miaofen Gu (Gu MF or Gu M) is reflected in some citations prior to 2000 instead of Miaofen G. Hu.
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