The role of the histone demethylase LSD1 in the pathogenesis of AML

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Despite novel therapeutic strategies, 50% of AML patients cannot achieve long-term remissions and succumb to their disease. The current model of AML pathogenesis proposes that a healthy hematopoietic stem cell (HSC) incurs several mutations to become a pre-leukemic stem cell (pre-LSC) and subsequently a leukemia initiating cell (LIC) from which the leukemic bulk cells evolve. Failure of our current therapies is attributed to eradication of the leukemic bulk but not the LICs. However, we lack knowledge of the changes that give rise to LICs and of their resistance mechanisms, both critical to achieving long-term remissions / functional cures. We have established a novel murine AML model by deletion of the lysine specific methylase LSD1 and subsequent bone marrow transplantation of LSD1 deficient cells. Single cell analyses from these mice define cells that represent healthy HSCs as well as all three aforementioned developmental stages of AML: pre-LSCs, LICs and an AML bulk. We propose to use data from these single cell analyses to determine the molecular changes that determine progression from HSC to pre-LSC and LIC as well as the differences between LICs and the leukemic bulk in LSD1 deficient AML.