PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

Abstract

Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their co-expression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study we demonstrate that co-expression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3 or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.

PBX3 is essential for leukemia stem cell maintenance in MLL‐rearranged leukemia

“…Previous studies reported that PBX3 interacts with MEIS1 and acts as a critical cofactor of HOXA9 in leukemogenesis . Here, we measured the Hoxa9 and Meis1 expression levels in L‐GMPs.…”

“…PBX3 have been proven to form a dimer with MEIS1 to evoke the full transforming activity of HOXA9 . Most surprisingly, ectopic expression of both PBX3 and MEIS1 was sufficient to transform normal hematopoietic stem/progenitor cells (HSPCs) and induce AML in mice . These data led us to hypothesize that TALE family members might play more significant roles than simply functioning as cofactors for HOXA genes in MLL ‐r leukemia.…”

“…Although it was demonstrated that co‐expression of Pbx3 with either Meis1 or Hoxa9 is sufficient to transform normal murine HSPCs and to recapitulate the phenotype caused by ectopic expression of MLL ‐fusion genes, the specific role of PBX3 in MLL ‐r leukemia progression is largely unknown. In this study, we found that high expression levels of PBX3 were both in AML patient samples and in LSCs of MLL ‐r induced AML mouse models.…”

Deregulation of the HOXA9/MEIS1 axis in acute leukemia

“…This MEIS1/PBX3 dimerization is required for expression of HOXA9/MEIS1 target genes such as FLT3 and TRIB2 (71). Moreover, coexpression of MEIS1/PBX3 is sufficient to transform cells in culture and lead to formation of leukemia in vivo with similar latency to that of MLL-AF9 (72). Expression patterns in cells transformed by MEIS1/PBX3 are consistent with that of the MLL-AF9 core transcriptome, including upregulation of HOXA9 (72).…”

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

“…Studies have demonstrated that enforced expression of MLL‐AF9 fusion protein could transform the non–self‐renewing granulocyte/macrophage progenitors (GMP) into leukemia stem cells (LSC) by activating the expression of Hox proteins . Consistently, the coexpression of Homeobox proteins Hoxa9/Meis1 or Meis1/Pbx3 is sufficient to immortalize hematopoietic progenitor cells (HPC) and induce leukemogenesis, indicating a bridge/mediator role of transcription factors in MLL fusion‐induced leukemic transformation and progression.…”