Targeting leukemic stem cells in acute myeloid leukemia

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Project Summary Acute myeloid leukemia (AML) is a clonal hematological malignancy with limited therapeutic options. It originates from and is sustained by a small population of self-renewing precursor cells - leukemia initiating/stem cells (LSCs). This immortal reservoir of tumor cells displays extremely low proliferation rates and resistance to current treatments. They are also responsible for relapses. It remains a critical challenge to develop effective therapeutics to eradicate LSCs. A novel approach focused on the unique characteristics and vulnerabilities of LSCs is needed in order to address this problem. We previously discovered a bioenergetic stress-induced differentiation/repopulation checkpoint in hematopoietic stem cells (HSCs) in studying PTPMT1, a mitochondria- based phosphoinositide phosphatase. Knockout of PTPMT1 decreases mitochondrial metabolism and causes bioenergetic stress, which in turn triggers a cell cycle checkpoint (AMPK-p21/p57), leading to differentiation- associated cell cycle arrest in HSCs. Importantly, the survival and self-renewal of these knockout HSCs are not affected, and their differentiation block is reversible. Our recent preliminary study suggests that a similar bioenergetic stress-induced cell cycle checkpoint may also operate in LSCs --- the development and maintenance of oncogene (FLT3-ITD and MLL-AF9)-driven or PTEN loss-induced AML are substantially inhibited by the deletion of PTPMT1. Interestingly, PTPMT1 depletion induces cell death in LSCs, in sharp contrast to HSCs. Mechanistically, PTPMT1 loss does not impact mitochondrial structure; rather, it appears to block mitochondrial utilization of the major metabolic substrate pyruvate, a key metabolite derived from glucose that lies at the intersection of mitochondrial oxidation and cytosolic fermentation. Based on these observations, we hypothesize that LSCs can be targeted by inducing bioenergetic/metabolic stress and cell cycle arrest through pharmacological inhibition of PTPMT1 or mitochondrial uptake of pyruvate, which yields the possibility of eradicating LSCs. Notably, alexidine dihydrochloride, an antibiotic used as an anti-septic and anti-plaque agent for dental products, has been identified as a selective and potent PTPMT1 inhibitor, and rosiglitazone (Avandia), a viable anti-type 2 diabetic drug (previously known as a peroxisome proliferator-activated receptor γ agonist), has been shown to effectively inhibit the mitochondrial pyruvate carrier/transporter (MPC). As a result, the novel properties of these drugs will serve as a critical asset for testing our hypothesis. We plan to achieve the objective of this proposal by pursuing the following three aims. 1). To further characterize the effects of PTPMT1 depletion on LSCs. 2). To determine the molecular mechanisms by which PTPMT1 depletion inhibits mitochondrial metabolism. 3). To test for the potential therapeutic effects of the PTPMT1 inhibitor alexidine dihydrochloride and the MPC inhibitor rosiglitazone in xenograft models of human AML. This project, if successful, may lead to a novel strategy to deplete LSCs in AML, and the PTPMT1 and MPC inhibitors could be repurposed and further developed into therapeutic agents for AML.