Deregulation of the HOXA9/MEIS1 axis in acute leukemia

Abstract

Purpose of review HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, where its over expression is strongly correlated with poor prognosis. This review highlights recent advances in the understanding of genetic alterations leading to deregulation of HOXA9 and the downstream mechanisms of HOXA9-mediated transformation. Recent findings A variety of genetic alterations including MLL-translocations, NUP98-fusions, NPM1 mutations, CDX deregulation, and MOZ-fusions lead to high level HOXA9 expression in acute leukemias. The mechanisms resulting in HOXA9 over expression are beginning to be defined and represent attractive therapeutic targets. Small molecules targeting MLL-fusion protein complex members, such as DOT1L and menin, have shown promising results in animal models, and a DOT1L inhibitor is currently being tested in clinical trials. Essential HOXA9 cofactors and collaborators are also being identified, including transcription factors PU.1 and C/EBPα, which are required for HOXA9-driven leukemia. HOXA9 targets including IGF1, CDX4, INK4A/INK4B/ARF, mir-21 and mir-196b and many others provide another avenue for potential drug development. Summary HOXA9 deregulation underlies a large subset of aggressive acute leukemias. Understanding the mechanisms regulating the expression and activity of HOXA9, along with its critical downstream targets, shows promise for the development of more selective and effective leukemia therapies.

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

“…Both NUP98 fusions, which have recently been shown to be dependent on MLL1 for leukemic transformation, 25 as well as CALM-AF10 fusions lead to overexpression of HOXA7/9/10 (referred to as a "HOXA" cluster), which is thought to be a final common pathway leading to poor prognosis AML in both humans and mice. 18,23,26,27 To broaden the models of hematopoietic malignancy evaluated, we studied a murine model of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) that was induced by overexpression of Lin28b. 28 Overexpression of LIN28B, or the closely related LIN28A, is seen in over 50% of patients with PTCL-NOS.…”

“…CALM‐AF10 fusions are associated with AML and immature T‐ALL in humans; the AML in both human patients and engineered murine models are characterized by clonal rearrangements of both IG and TCR genes, suggesting that the cell of origin is multipotent. Both NUP98 fusions, which have recently been shown to be dependent on MLL1 for leukemic transformation, as well as CALM‐AF10 fusions lead to overexpression of HOXA7/9/10 (referred to as a “ HOXA ” cluster), which is thought to be a final common pathway leading to poor prognosis AML in both humans and mice . To broaden the models of hematopoietic malignancy evaluated, we studied a murine model of peripheral T cell lymphoma, not otherwise specified (PTCL‐NOS) that was induced by overexpression of Lin28b .…”

Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia

“…HOXA9 and MEIS1 have been widely reported to be important contributors to the progression of AML (9,10). The synergistic effect of HOXA9 and MEIS1 also leads to the development of aggressive AML with poor prognosis.…”

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

“…For example, MEIS1 has been shown to regulate genes in the NOTCH pathway [40] and sensitizes cells to TNF [41]. Moreover, MEIS1 is essential for the expression of genes driven by the HOXA9-NUP98 fusion in acute myeloid leukemia [42][43][44].…”