NON-GENETIC MECHANISMS OF CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA

Acute Myeloid Leukemia (AML) is the most common type of acute hematological malignancy in adults. 40–60% of patients relapse due to the emergence of cellular resistance to anti- leukemic drugs. Drug resistance in leukemic cells has been associated with intratumoral heterogeneity, among which quiescence, specifically, is considered a key factor for cell survival. Experimental evidence collected both from patients and model systems suggests that relapse is due to rare persistent AML cells which survive chemotherapy. Chemotherapy persistent cells are not yet biologically and molecularly defined. Open questions are whether persistent cells are drug-resistant, what are their cellular and molecular features, as well as their content in leukemic stem cells. My working hypothesis is that chemoresistance in AMLs is associated with specific phenotypic states that characterize rare cell populations found within the pool of quiescent leukemic cells. These cells are selected by chemotherapy and represent the cellular basis of the relapse. To test my hypothesis, I explored transcriptional and functional characteristics of quiescent leukemic cells and tested the effect of chemotherapy. Here, I present two newly established xeno-models of chemoresistant human AMLs that closely recapitulate clinical data. My data show that quiescent cells accumulate over time and quiescent and proliferating cells can switch from one state to another. Notably, quiescent cells are selectively spared by chemotherapy and show resistance to additional rounds of treatment. Finally, quiescent cells appear as the only carrier of tumorigenic capacity in AMLs and are, therefore, deemed essential for leukemia development and, possibly, relapse.