Ernst Laboratory - Hematopoietic transformation in the absence of

Journal article

Yufei Chen, P. Ernst
Cell Cycle, 2019

Cite

APA Click to copy
Chen, Y., & Ernst, P. (2019). Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation. Cell Cycle.

Chicago/Turabian Click to copy
Chen, Yufei, and P. Ernst. “Hematopoietic Transformation in the Absence of MLL1/KMT2A: Distinctions in Target Gene Reactivation.” Cell Cycle (2019).

MLA Click to copy
Chen, Yufei, and P. Ernst. “Hematopoietic Transformation in the Absence of MLL1/KMT2A: Distinctions in Target Gene Reactivation.” Cell Cycle, 2019.

BibTeX Click to copy

@article{yufei2019a,
  title = {Hematopoietic transformation in the absence of MLL1/KMT2A: distinctions in target gene reactivation},
  year = {2019},
  journal = {Cell Cycle},
  author = {Chen, Yufei and Ernst, P.}
}

Abstract

ABSTRACT The deregulation of hematopoietic stem cell (HSC) transcriptional networks is a common theme in acute myelogenous leukemia (AML). Chromosomal translocations that alter the Mixed Lineage Leukemia 1 gene (MLL1, MLL, KMT2A) occur in infant, childhood and adult leukemia and at the same time, wild-type MLL1 is a critical regulator of HSC homeostasis. Typically, the endogenous, wild-type (WT) MLL1 and MLL fusion oncoproteins (MLL-FPs) remain both expressed in leukemia. WT and MLL-FPs activate overlapping sets of target genes, presenting a challenge for the selective therapeutic targeting of leukemic cells. We previously demonstrated that endogenous MLL1 is not required for the maintenance of MLL-FP-driven AML but is required for normal HSC homeostasis. Here we address the role of MLL-FPs in the initiation of leukemia in the absence of endogenous MLL1. We show that loss of endogenous Mll1 results in a rapid decrease in expression of shared HSC/leukemia target genes, yet MLL-AF9 restores the expression of most of these target genes in the absence of WT MLL1, with the critical exception of Mecom/Evi1. These observations underscore the sufficiency of MLL-fusion oncoproteins for initiating leukemia, but also illustrate that WT MLL1 target genes differ in their ability to be re-activated by MLL-FPs.