Glutamine addiction is a therapeutic target to block emergency myelopoiesis

Abstract

Inflammation-driven emergency myelopoiesis (EM) contributes to the progression of many solid cancers and inflammatory diseases, yet therapeutic strategies to selectively suppress EM without compromising hematopoiesis remain lacking. Here, we use functional and single-cell transcriptomic analyses to determine metabolic programs organizing the hematopoietic hierarchy, myeloid lineage commitment, and myeloid differentiation. We identify de novo glutamine biosynthesis as a stem cell-specific survival mechanism allowing independence from exogenous glutamine. We show that myeloid differentiation is characterized by Myc-driven upregulation of mitochondrial respiration, which is hyperactivated during EM and renders myeloid progenitors dependent on glutaminolysis to fuel the TCA cycle. Both genetic and pharmacologic targeting of glutaminase suppresses EM and impairs breast tumor progression by reducing intratumoral neutrophil infiltration. Our study defines a central role for Myc-glutaminolysis in driving EM, identifies glutaminolysis as a therapeutic target to normalize maladaptive EM, and highlights myeloid overproduction as a systemic problem requiring HSPC targeting. HIGHLIGHTSO_LIHSC survival depends on de novo glutamine biosynthesis via glutamine synthetase C_LIO_LIMyc hyperactivation drives mitochondrial biogenesis during emergency myelopoiesis C_LIO_LIMyeloid progenitors become glutamine-addicted to fuel Myc-driven TCA cycle activity C_LIO_LIGlutaminase deficiency in HSPCs blunts tumor-promoting neutrophil production C_LI ETOC BLURBOlson et al. show that emergency myelopoiesis, the inflammatory overproduction of myeloid cells that drives regeneration, depends on Myc-driven mitochondrial respiration and glutamine addiction in hematopoietic progenitors. Targeting glutaminase in hematopoietic stem and progenitor cells suppresses pathological myelopoiesis, reduces tumor-promoting neutrophil production, and slows breast tumor growth.