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Translocation (8;21) is one of the most common cytogenetic abnormalities in acute myeloid leukemia (AML). It leads to the formation of a fusion protein named AML1-ETO; this fusion protein is generally recognized as a repressor of endogenous AML1, which is essential for definitive hematopoietic stem cell emergence and lineage differentiation. AML1-ETO inhibits hematopoietic cell differentiation and promotes a self-renewal phenotype.
Our lab utilizes the retroviral gene transfer technique to introduce AML1-ETO fusion gene into human umbilical cord blood-derived hematopoietic stem and progenitor cells (CD34+). This allows us to study the molecular mechanisms of self-renewal associated with AML1-ETO expression and to explore the mechanisms whereby AML1-ETO promotes leukemogenesis. We have recently observed that AML1-ETO expression causes repression of genes involved in various DNA damage repair pathways. As a result, AML1-ETO-expressing hematopoietic cells intrinsically accumulate DNA damage and mutations, even in the absence of acute stress and show an increased expression of p53, the master responder to DNA damage.
Our current goal is to understand how these AML1-ETO expressing cells adapt to these intrinsic stresses. Our initial findings suggest a critical role for antiapoptotic Bcl-xL expression in these cells, potentially downstream of the thrombopoietin / MPL signaling pathway. A thorough understanding of the survival signaling may provide insight into the pathogenesis of t(8;21) AML and alternative strategies to treat this disease.
A class II mutation involved in transformation of hematopoietic stem and progenitor cells is thought to impart a block in differentiation leading to enhanced self-renewal. We propose that a critical aspect of this self-renewal signal is an intrinsic survival signal, which, in the case of the Tpo / MPL signal, is imparted by the Bcl-xL protein.
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