Myc Driven Emergency Myelopoiesis Reprograms HPSC Metabolism

Hematopoietic stem and progenitor cells (HSPC) respond to infections, inflammation, and regenerative challenges using cellular and molecular mechanisms termed emergency myelopoiesis (EM) pathways. Here, we sought to understand the metabolic adaptation by which EM reprograms HSPCs to oveproduce myeloid cells under stress conditions. Analysis of HSPC scRNAseq response to EM activation identified Myc driven transcriptionally reprograming leading to increased OXPHOS and dependence on glutaminolysis and anaplerotic glutamine metabolism. We uncover glutaminase as a prime target to suppress myeloid overproduction under conditions of maladaptive EM, such as during breast cancer development. Collectively, our work illuminates fundamental metabolic regulatory mechanisms in hematopoietic regeneration and identifies a common Myc-driven EM adaptation that results in therapeutically targetable 'glutamine addicition'.