Transcriptional reprogramming in neonatal hematopoietic stem and progenitor cells

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Hematopoietic stem cells (HSCs) and lineage-committed hematopoietic progenitor cells (HPCs) undergo profound shifts in gene expression during the neonatal and juvenile stages of life. Temporal changes in HSC/HPC gene expression underlie concomitant changes in self-renewal capacity, lineage biases, and hematopoietic output. Moreover, they can modify disease phenotypes. For example, childhood leukemias have distinct driver mutation profiles relative to adult leukemias, and they may arise from distinct cells of origin. The putative relationship between neonatal HSC/HPC ontogeny and childhood blood disorders highlights the importance of understanding how, at a mechanistic level, HSCs transition from fetal to adult transcriptional states. In this perspective piece, we summarize recent work indicating that the transition is uncoordinated and imprecisely timed. We discuss implications of these findings, including mechanisms that might enable neonatal HSCs and HPCs to acquire adultlike properties over a drawn-out period, in lieu of precise gene regulatory networks. The transition from fetal to adult transcriptional programs coincides with a pulse of type I interferon signaling that activates many genes associated with the adultlike state. This pulse may sensitize HSCs/HPCs to mutations that drive leukemogenesis shortly after birth. If we can understand how developmental switches modulate HSC and HPC fate after birth—both under normal circumstances and in the setting of disease-causing mutations—we can potentially reprogram these switches to treat or prevent childhood leukemias.

Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalExperimental Hematology
StatePublished - Sep 2021


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