AML: an insight into quiescence regulation, disease progression and chemoresistance

Acute myeloid leukemia (AML) is the most common leukemia in adults. AML is hierarchically organized, at the apex Leukemia Stem Cells (LSCs), a rare cell population able to initiate and sustain the tumor, that share selfrenewal capacity and quiescence properties with normal Hematopoietic Stem Cells. Quiescent LSCs can survive to chemotherapy, leading to leukemia relapse, the major cause of death for AML patients. So, up to now the mayor need for this pathology is the identification of the molecular mechanisms underlying drug resistance and disease progression. Therefore, this project thesis aimed to: (i) identify genes that could be required for the maintenance of the quiescence state of leukemic stem cells, starting from an in vivo shRNA screening on murine AMLs. (ii) study whether of the E3 ubiquitin ligase WWP1 contributes to the chemoresistance of AML blasts. The results obtained indicate that: (i) Silencing of the transcriptional repressor GFI1 in MLL-AF9 murine blasts decreases their proliferation and colony-forming efficiency in vitro and completely abrogates their engraftment ability in vivo, thus preventing leukemia growth; (ii) WWP1 negatively influences the ability of AML cells to respond to various chemotherapics.