AHI-1: a novel signaling protein and potential therapeutic target in human leukemia and brain disorders
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1Terry Fox Laboratory, British Columbia Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
2Department of Medicine, University of British Columbia, Vancouver, BC, Canada V5Z 1L3
Received: December 23, 2011; Accepted: December 28, 2011; Published: December 30, 2011;
Keywords: AHI-1, oncogene, CML, CTCL, AHI-1-BCR-ABL-JAK2 interaction complex, tyrosine kinase inhibitors, leukemic stem cells, TKI resistance, Joubert syndrome and susceptibility gene
Dr. Xiaoyan Jiang, email:
Progress in the understanding of the molecular and cellular mechanisms of human cancer, including human leukemia and lymphomas, has been spurred by cloning of fusion genes created by chromosomal translocations or by retroviral insertional mutagenesis; a number of oncogenes and tumor suppressors involved in development of a number of malignancies have been identified in this manner. The BCR-ABL fusion gene, originating in a multipotent hematopoietic stem cell, is the molecular signature of chronic myeloid leukemia (CML). Discovery of this fusion gene has led to the development of one of the first successful targeted molecular therapies for cancer (Imatinib). It illustrates the advances that can result from an understanding of the molecular basis of disease. However, there still remain many as yet unidentified mutations that may influence the initiation or progression of human diseases. Thus, identification and characterization of the mechanism of action of genes that contribute to human diseases is an important and opportune area of current research. One promising candidate as a potential therapeutic target is Abelson helper integration site-1(Ahi-1/AHI-1) that was identified by retroviral insertional mutagenesis in murine models of leukemia/lymphomas and is highly elevated in certain human lymphoma and leukemia stem/progenitor cells. It encodes a unique protein with a SH3 domain, multiple SH3 binding sites and a WD40-repeat domain, suggesting that the normal protein has novel signaling activities. A new AHI-1-BCR-ABL-JAK2 interaction complex has recently been identified and this complex regulates transforming activities and drug resistance in CML stem/progenitor cells. Importantly, AHI-1 has recently been identified as a susceptibility gene involved in a number of brain disorders, including Joubert syndrome. Therefore, understanding molecular functions of the AHI-1 gene could lead to important and novel insights into disease processes involved in specific types of diseases. Ultimately, this knowledge will set the stage for translation into new and more effective diagnostic and treatment strategies.
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