The role of HOXB2 and HOXB3 in acute myeloid leukemia

Biochem Biophys Res Commun. 2015 Nov 27;467(4):742-7. doi: 10.1016/j.bbrc.2015.10.071. Epub 2015 Oct 22.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML.

Keywords: Acute myeloid leukemia; Colony formation; FLT3; HOXB2; HOXB3; STAT5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Leukemic
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mutation*
  • Phosphorylation / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • HOXB2 protein, human
  • Homeodomain Proteins
  • HoxB3 protein, human
  • Transcription Factors
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3