Loss of the metabolic sensor, PPARA, overcomes differentiation blockade and immune suppression in AML

ABSTRACT: The hematopoietic system balances self-renewal and differentiation in response to various environmental cues. The nuclear hormone receptor superfamily consists of ligand-activated transcription factors that allow cells to integrate external stimuli with cellular programs regulating differentiation, metabolism, proliferation and survival. We and others have shown that members of this family play central roles in normal, stress and malignant hematopoiesis. Here, we report that expression of PPAR-alpha is elevated in patients with high risk subtypes of acute myeloid leukemia (AML). On this basis, we hypothesized that genetic disruption of the alpha isoform of PPAR would selectively impair AML maintenance while sparing normal hematopoietic stem progenitor cells. Indeed, Ppara null MLL-AF9 leukemia displayed a relief of its differentiation blockade, a hallmark of acute leukemia. This restored differentiation was accompanied by gene expression patterns indicative of altered metabolic pathways and immune signaling. By contrast, steady-state and stress myelopoiesis were largely unaffected by the loss of Ppara with the exception of a mild increase in differentiated myeloid cells. Notably, a significant survival advantage was observed in Ppara deleted AML as compared to controls. In contrast, transplantation into Rag2-/- recipients substantially reduced this survival advantage, demonstrating dependence on the adaptive arm of the immune system. These results suggest possible therapeutic implications for immune modulation through pharmacologic targeting of PPARA signaling. Taken together, our in vivo studies of Ppara in MLL-AF9 AML are consistent with a model in which concomitant regulation of cell-intrinsic programs and modulation of interactions with the leukemic immune microenvironment by PPARA promotes leukemia maintenance.

ORGANISM(S): Mus musculus

PROVIDER: GSE158938 | GEO | 2020/10/03

REPOSITORIES: GEO