The chromatin reader protein MLLT1 is critical to maintain normal B lymphopoiesis

Prakash, J.; Achille, N. J.; Adelman, E. R.; Zhang, S.; Bushweller, J. H.; Figueroa, M. E.; Hemenway, C. S.; Zeleznik-Le, N. J.

doi:10.64898/2026.08.08.743534

bioRxiv · 10.64898/2026.08.08.743534

The chromatin reader protein MLLT1 is critical to maintain normal B lymphopoiesis

Prakash, J.·Achille, N. J.·Adelman, E. R.·Zhang, S.·Bushweller, J. H.·Figueroa, M. E.·Hemenway, C. S.·Zeleznik-Le, N. J.

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Abstract

MLLT1 (also named ENL) is a chromatin reader protein whose encoding gene was originally identified as a chromosomal translocation partner with MLL(KMT2A) in acute leukemia. However, its role in normal hematopoiesis has not been investigated. This study uncovers a critical role of Mllt1 in normal B cell lymphopoiesis. We found Mllt1 to be essential for early B lymphocyte development using a conditional Mllt1 knockout mouse model that we developed. A significant decrease of bone marrow B-lineage progenitors, splenic transitional B cells and peripheral blood B cells were observed in Mllt1del mice compared to control Mllt1fl/fl mice. Similarly, Mllt1 deletion in in vitro cultured B-enriched progenitor cells from Mllt1fl/fl; Rosa26CreERT2/+ mice resulted in reduced B cells, demonstrating the cell-intrinsic role of Mllt1 in this process. Direct MLLT1 target genes including Il7r and critical B-lineage transcription factors, Ebf1 and Pax5, were decreased following Mllt1 deletion. Gene set enrichment, gene ontology, and functional analyses of Mllt1-deficient cells showed significant alterations related to B cell development, critical relevant signaling pathways, DNA replication, and mitochondrial function. In vitro complementation with MLLT1 rescued the B cell phenotype observed with endogenous Mllt1 deletion; however, specific MLLT1 YEATS domain mutants lacking chromatin reader and RNA-binding functions were unable to rescue the phenotype. Taken together, our research demonstrates a previously unappreciated role for MLLT1 as critical for maintenance of B cell lymphopoiesis.

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Prakash, J., Achille, N. J., Adelman, E. R., Zhang, S., Bushweller, J. H., Figueroa, M. E., Hemenway, C. S., Zeleznik-Le, N. J.. 2026-08-10. The chromatin reader protein MLLT1 is critical to maintain normal B lymphopoiesis. https://doi.org/10.64898/2026.08.08.743534

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