The role of HOXB2 and HOXB3 in acute myeloid leukemia.
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.
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden; Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
Oscar
O
Lindblad
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Rohit A
RA
Chougule
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Sausan A
SA
Moharram
Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
Nuzhat N
NN
Kabir
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Jianmin
J
Sun
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden; Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
Julhash U
JU
Kazi
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden. Electronic address: lars.ronnstrand@med.lu.se.
Lars
L
Rönnstrand
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C086061:HOXB2 protein, human; D018398:Homeodomain Proteins; C542921:HoxB3 protein, human; D014157:Transcription Factors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
Acute myeloid leukemia; Colony formation; FLT3; HOXB2; HOXB3; STAT5