MLLT3/AF9 is Pivotal for Human HSC Self-renewal and Engraftment

A major goal of stem cell and regenerative medicine researchers is to culture human hematopoietic stem cells (HSCs) for transplantation purposes, which has been hindered by insufficient mechanistic knowledge of HSC self-renewal. In their recent Nature study, Calvanese et al. identify the chromatin reader/activator MLLT3/AF9 as a pivotal regulator of HSC maintenance. Though lost during culture, MLLT3 expression is normally enhanced in human fetal, neonatal, and adult HSCs. The authors used various approaches to demonstrate that human hematopoietic stem or progenitor cells (HSPCs) are not sustainable in culture following MLLT3 depletion, whereas MLLT3 overexpression resulted in a 12-fold amplification of HSCs capable of multilineage regeneration in mouse transplantation recipients. Chromatin interrogation revealed that MLLT3 binds to the transcriptional start sites (TSSs) of active HSPC gene regions enriched for H3K79me2, indicating that MLLT3 works with DOT1L in human HSCs to increase this chromatin mark and perpetuate active gene expression during expansion in culture. The authors stressed that MLLT3 appears to preserve, rather than instill, HSC stemness orchestrated by other transcription factors, hopefully mitigating the risk of leukemogenesis. Thus, MLLT3 appears to be a key regulator of a set of factors responsible for establishing a specific chromatin state in HSC regulatory genes that facilitates the generation of an expandable and engraftable HSC population capable of multilineage reconstitution.

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