HoxA9 induces insulin-like growth factor-1 receptor expression in B-lineage acute lymphoblastic leukemia.
The homeobox (Hox) gene family encodes a group of transcription factors preferentially expressed during embryonic development and hematopoiesis. Deregulation of Hox gene expression is frequently associated with acute leukemia. HoxA9 is the most commonly overexpressed Hox gene in acute leukemia. However, little is known regarding specific pathways regulated by HoxA9 that promote the growth and survival of leukemic cells. We have generated a conditional model of HoxA9 activity in the stromal cell dependent, HoxA9 negative, pre-B-cell line B-lineage-2 (BLIN-2). Conditional HoxA9 activation in BLIN-2 resulted in increased proliferation in the presence and absence of stromal cell support. Stimulation of HoxA9 activity resulted in increased expression of the c-Myb transcription factor and induction of insulin-like growth factor-1 receptor (IGF-1R) surface expression. HoxA9-mediated proliferative effects in BLIN-2 cells were abrogated when the cells were treated with specific IGF-1R tyrosine kinase inhibitors or with an IGF-1R mAb (A12). IGF-1R expression correlated with endogenous HoxA9 expression in a small panel of mixed lineage leukemia (MLL)/AF4 cell lines. siRNA knockdown of endogenous HoxA9 expression in the MLL/AF4-positive cell line RS4;11 resulted in loss of IGF-1R expression. These data indicate that HoxA9 overexpression induces IGF-1R expression and subsequently promotes leukemic cell growth.
Whelan
J T
JT
Department of Microbiology and Immunology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA.
Ludwig
D L
DL
Bertrand
F E
FE
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015139:Blotting, Southern; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018398:Homeodomain Proteins; C113855:MLL-AF4 fusion protein, human; C489427:MYC protein, human; D015514:Oncogene Proteins, Fusion; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1