Microarray analysis of NGF/TrkA-induced genes in the human mast cell leukemia cell line HMC-1 identifies novel TrkA target genes which support survival and/or proliferation

The role of nerve growth factor (NGF) receptor TrkA in neuronal differentiation is well characterized. However, TrkA has also been connected with cancer malignancy in leukemia, breast cancer, or hepatocellular carcinoma. Recently, we demonstrated that NGF/TrkA can rescue chronic myelogenous leukemia (CML) cells and the human mast cell leukemia cell line HMC-1 which is transformed by a mutant SCF-receptor, c-Kit (V560G), from cell death induced by Abl/c-Kit tyrosine kinase inhibitor imatinib mesylate. Moreover, imatinib/NGF treated HMC-1 cells proliferate nearly as well as untreated cells. To examine TrkA-mediated proliferation and survival in these cells, we analyzed NGF-induced gene expression by a microarray approach. We identified KLF2 and SMAD7 as novel TrkA downstream genes and a knockdown of KLF2 gene expression by siRNA revealed that the transcription factor is involved in survival signaling in HMC-1 cells.

In addition, expression of the homeodomain containing transcription factor HOXB8 was upregulated by NGF and downregulated by imatinib treatment in our microarray. Knockdown of HOXB8 by lentivirally delivered shRNA slowed cell growth 2 to 3 weeks after infection in the CML cell line K562 indicating that HOXB8 may play a role for proliferation of these cells. However, using a cancer cell line cDNA profiling array (Clontech), we found that HOXB8 is also present in cell lines which are derived from solid cancer such as SK-OV-3, HCT-15 or HCT116.