Tumor necrosis factor from leukemic environment stimulates hematopoietic stem/progenitor cells toward megakaryocyte/myeloid lineage bias

Acute myeloid leukemia (AML) is characterized by the proliferation of malignant myeloid progenitor cells and impairment of hematopoiesis. Although genetic abnormalities within leukemic cells have been investigated in detail, definitive explanations for the damage to the normal hematopoietic system are lacking. Here, we investigated the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow in AML. We evaluated the function of residual nonleukemic (nl)-hematopoietic stem/progenitor cells (HSPCs) from the bone marrow of mice with MLL-AF9-induced AML. The nl-HSPCs in the leukemic marrow showed a megakaryocyte (MgK) and myeloid-biased gene expression signature, with enrichment of tumor necrosis factor (TNF) signaling and reduced repopulation ability. To investigate whether the upregulation of TNF signaling causes the MgK/myeloid lineage bias, we investigated the effects of TNF-α in normal hematopoietic stem cells (HSCs)/HSPCs under ex vivo expansion condition. Single-cell transcriptome analysis of these cells revealed an increased frequency of cells expressing genes related to the MgK lineage and decreased repopulation capacity compared with those of ex vivo expanded HSCs/HSPCs without TNF-α. Our data suggest that increased TNF-α in the leukemic bone marrow environment at least in part drives HSPCs toward MgK/myeloid differentiation, resulting in the exhaustion of residual normal HSCs/HSPCs. These findings offer valuable insights into leukemic biology and normal hematopoiesis.