Hepatic Leukemia Factor supports the propagation of leukemia and hematopoietic stem cell function during stress-induced regeneration.

The processes regulating hematopoietic stem cells (HSC) during aging are not fully understood1, but it is clear that the incidence of hematological malignancies increases with age, highlighting the importance of unravelling the cellular and molecular networks involved. Recently, we identified Hepatic Leukemia Factor (HLF) as an essential transcription factor in maintaining the HSC pool during regeneration2 and showed that failure to downregulate HLF leads to disrupted differentiation3. Here, we found that HLF is dispensable for hematopoiesis during systemic aging, but needed during stress-induced hematopoietic recovery of aged HSC after transplantation. Additionally, HLF was dispensable for leukemic initiation but required for disease propagation. Taken together, our findings demonstrate the existence of a HLF-dependent mechanism that uncouples stress-induced regeneration from hematopoietic homeostasis during aging, that can be used by malignant cells to gain stem cell properties to propagate the disease. Key pointsO_LIHLF is dispensable for HSC function and hematopoietic homeostasis during physiological aging, but crucial during stress induced regeneration. C_LIO_LIHLF supports the propagation of leukemia-initiating cells C_LI