Abstract
HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, BCL2 and SOX4 synergistically induced leukemia with MYC. Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.
Highlights
Mutations of transcriptional regulators often cause aberrant gene regulation of hematopoietic cells, which leads to leukemia
We reveal the oncogenic roles for HOXA9 and its target gene products in leukemogenesis and its unique mode of function as a transcriptional maintenance factor which preserves an identity of a hematopoietic precursor
We analyzed leukemia cells (LCs) harvested from mice suffering from MLL-AF10-induced leukemia (MLL-AF10-LCs) and immortalized cells (ICs) transformed by MLL and ENL (MLL-ENL) ex vivo (MLL-ENL-ICs)
Summary
Mutations of transcriptional regulators often cause aberrant gene regulation of hematopoietic cells, which leads to leukemia. Structural alterations of the mixed lineage leukemia gene (MLL known as KMT2A) by chromosomal translocations cause malignant leukemia that often associates with poor prognosis despite the current intensive treatment regimens [1]. MLL encodes a transcriptional regulator that maintains segment-specific expression of homeobox (HOX) genes during embryogenesis [2], which determines the positional identity within the body [3,4,5]. MLL maintains the expression of posterior HOXA genes and MEIS1 (another homeobox gene), which promote the expansion of hematopoietic stem cells and immature progenitors [6,7,8,9,10]. HOXA9 and MEIS1 are highly transcribed in MLL-rearranged leukemia [7].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
