Lymphoid lineage developmental potential of fetal and adult hematopoietic progenitors is differentially programmed via CBFβ2 gene dosage 4356

Abstract Description Hematopoiesis tightly regulates the differentiation of stem cells into various immune lineages. The RUNX-CBFβ transcription factor complex plays a pivotal role in this process. CBFβ2 isoform uniquely directs the development of innate-like lymphocytes, such as γδT cells. Using Cbfb2 heterozygous (HET) we uncovered crucial insights into how CBFβ2 regulates Tγδ17 cell generation. Our results demonstrate that neonatal Tγδ17 cells persist in HET mice despite reduced fetal thymic precursors, indicating compensatory mechanisms. Adult bone marrow progenitors, typically inefficient at generating Tγδ17 cells, displayed enhanced lineage commitment potential when a single copy of Cbfb2 was present. Overexpression of CBFβ2 in these progenitors suppressed this activity, underscoring the dosage-dependent regulatory effects of CBFβ2 on lineage plasticity. Transcriptomic analyses revealed increased expression of embryonic hematopoiesis-associated genes, including Sox6, in HET lymphoid-primed multipotent progenitors. Furthermore, in utero transplantation of adult HET progenitors into E14.5 fetal liver revealed improved reconstitution of neonatal-origin Tγδ17 cells, highlighting their reprogramming potential under reduced Cbfb2 expression. Our findings position CBFβ2 as a key regulator of temporal hematopoietic plasticity and suggest its utility in reprogramming adult progenitors to generate fetal-like lymphocytes, offering promising avenues for therapeutic use of hematopoietic reprogramming. Funding Sources NIH/NIAID R21 AI159457 Topic Categories Hematopoiesis and Immune System Development (HEM)