Acute myeloid leukemia (AML) is the deadliest type of acute leukemia with a 5-year survival rate of 27% and only 5~10% for patients over the age of sixty. Development of resistance to chemotherapy and posttreatment relapse remain the major obstacles for curative therapies. The high rate of relapse in AML has been attributed to the presence of leukemia stem cells (LSCs); however, the molecular characteristics controlling LSC activity in AML pathophysiology and therapy response remain unclear. This poses a major barrier for developing more effective therapies to selectively eliminate LSCs to prevent disease progression and/or relapse. The role of mobile DNA elements in human cancer has been hi...

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Acute myeloid leukemia (AML) is the deadliest type of acute leukemia with a 5-year survival rate of 27% and only 5~10% for patients over the age of sixty. Development of resistance to chemotherapy and posttreatment relapse remain the major obstacles for curative therapies. The high rate of relapse in AML has been attributed to the presence of leukemia stem cells (LSCs); however, the molecular characteristics controlling LSC activity in AML pathophysiology and therapy response remain unclear. This poses a major barrier for developing more effective therapies to selectively eliminate LSCs to prevent disease progression and/or relapse.

The role of mobile DNA elements in human cancer has been historically underappreciated both because they have been dismissed as "junk" DNA and because their variation poses unique challenges. As the only autonomous mobile DNA in the genome, retrotransposons are considered mostly detrimental because their mobility can cause genetic mutations that contribute to human cancer. We recently discovered that suppression of retrotransposons is selectively required for the propagation of AML cells and associates with therapy resistance and poor prognosis in AML patients. These findings establish a new and unexpected "tumor-suppressive" role for retrotransposons as a targetable dependency of LSCs.

The goals of this project are to establish the requirement of retrotransposons in clinically relevant AML models, to determine the mechanisms by which retrotransposons contribute to AML development, and to investigate the role of retrotransposons in modulating AML therapy response. Together these studies will not only elucidate the underlying basis for retrotransposons in the malignant propagation of leukemia stem cells, but also establish a previously uncharted biological pathway for overcoming therapy resistance, thus enabling the development of improved anti-leukemia therapies especially for high-risk chemotherapy-resistant myeloid leukemia.

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