In our study, we found miR-181a expression was negatively correlated with three HOXA genes and they were associated with AML risk status and prognosis in granulocytic AML.
To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL.
We found that HOTTIP is aberrantly activated in acute myeloid leukemia (AML) to alter HOXA-driven topologically associated domain (TAD) and gene expression.
Although transcript levels are very low in normal human bone marrow cells, high IRX3 expression is found in ∼30% of patients with acute myeloid leukemia (AML), ∼50% with T-acute lymphoblastic leukemia, and ∼20% with B-acute lymphoblastic leukemia, frequently in association with high-level HOXA gene expression.
In general, somatic SETBP1 mutations have a significant clinical impact on the outcome as poor prognostic factor, due to downstream HOXA-pathway as well as associated aggressive types of chromosomal defects (-7/del(7q) and i(17q)), which is consistent with wild-type SETBP1 activation in aggressive types of acute myeloid leukemia and leukemic evolution.
To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells.
These data support a role of AP-2α in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival.
Because HoxA proteins had not been previously known to influence expression of pro-proliferative cytokines, this has implications for understanding molecular mechanisms involved in progenitor expansion and the pathobiology of AML.
These findings suggest that a key characteristic of poor prognosis acute myeloid leukemia is increased, differentiation-stage inappropriate expression of the Abd HoxA proteins and their DNA-binding partners.
The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9.