TAZ-mediated mitochondrial phospholipid production regulates AML cell stemness and clonogenicity.

  • Major Finding: TAZ-mediated mitochondrial phospholipid production regulates AML cell stemness and clonogenicity.

  • Mechanism: TAZ suppresses intracellular levels of phosphatidylserine, which in turn suppresses TLR activity.

  • Impact: Inhibition of mitochondrial phospholipid production could be therapeutically efficacious in AML.

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Acute myeloid leukemia (AML) cells possess unique mitochondrial and metabolic features, including an increased reliance on oxidative phosphorylation. Seneviratne, Xu, and colleagues sought to exploit this distinguishing feature of AML cells, and thus performed a genome-wide CRISPR knockout screen to identify mitochondrial genes that are required for AML cell growth and viability. Among the top depleted genes was TAZ, which encodes a mitochondrial transacylase that is required for the production of the mitochondrial phospholipid cardiolipin under physiologic conditions. TAZ depletion in leukemia cell lines was associated with an increase in genes associated with myeloid differentiation and a concomitant decrease in stem/progenitor cell–associated genes. Furthermore, TAZ knockdown reduced the clonogenic growth of AML cells in vitro. No discernable effect of TAZ depletion on normal steady-state hematopoiesis and stem-cell function was observed, indicating that the consequences of TAZ loss are leukemia cell–specific, but reduced numbers of hematopoietic stem cells were observed after 5-FU–induced cellular stress. In addition to cardiolipin, TAZ knockdown in AML cells also altered levels of intracellular phospholipids, and led to increased levels of phosphatidylserine (PS). Increased intracellular PS or TAZ knockdown increased AML differentiation and reduced clonogenic growth and engraftment in vivo in association with increased Toll-like receptor (TLR) activity. Moreover, inhibition of PS decarboxylase, which converts PS to phosphatidylethanolamine in the inner mitochondrial membrane and also binds cardiolipin, reduced clonogenic growth of AML cells. This work collectively uncovers the therapeutic potential of exploiting phospholipid metabolism in AML.

Seneviratne AK, Xu M, Aristizabal Henao JJ, Fajardo VA, Hao Z, Voisin V, et al. The mitochondrial transacylase, Tafazzin, regulates for AML stemness by modulating intracellular levels of phospholipids. Cell Stem Cell 2019;24:621–36.

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