An MLL-dependent network sustains hematopoiesis

EL Artinger, BP Mishra, KM Zaffuto… - Proceedings of the …, 2013 - National Acad Sciences
EL Artinger, BP Mishra, KM Zaffuto, BE Li, EKY Chung, AW Moore, Y Chen, C Cheng
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain
hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox
genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-
regulated genes in normal hematopoietic cells remains unknown. Here, we identify and
characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells
with an integrated approach by using conditional loss-of-function models, genomewide …
The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.
National Acad Sciences