MEDICAL HYPOTHESES AND RESEARCH
VOL. 7, No. 1/2, December 2011




M. Chi, et al. [2011] Med. Hypotheses Res. 7: 27−33.

A Dominant Genetic Mechanism for Acquired Imatinib-
Resistance of Blast Crisis Chronic Myeloid Leukemia

Martin Chi, Qiang Liu, Linling Chen, Yafan Wang, WenYong Chen,
Hongfeng Yuan, Tomas Radivoyevitch and Yun Yen*

Department of Molecular Pharmacology and Translational Research Core Laboratory (M.C.,
L.C., Y.W., Y.Y.), Department of Cancer Biology, City of Hope Beckman Research Institute
and National Medical Center, Duarte, CA 91010 (W.Y.C.), Department of Epidemiology and
Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA (T.R.)

Abstract. A dominant genetic mechanism is hypothesized and tested for acquired drug
resistance of blast crisis chronic myeloid leukemia, which is initially sensitive to imatinib but
shortly develops resistance due to genetic mutations. A cell line KCL-22 of blast crisis
chronic myeloid leukemia is exemplified, of which each cell contained two copies of
Philadelphia chromosome t(9;22) harboring the BCR-ABL fusion gene. When one of these
two copies in an individual cell was mutated to 315I, the cell was sufficient to become
imatinib resistant, suggesting a dominant genetic mechanism. This mechanism was also
supported by mathematical simulation of cell growth kinetics. Thus, the copy number of the
susceptible gene and the copy number of causative mutations are correlated with the
resistance phenomenon. Clinically, the copy number of a susceptible diploid or multi-ploid
gene due to cell fusion, gain of chromosomes, or gene amplification plays important roles in
drug resistance and serves as markers to guide therapeutic decisions.

* Correspondence:  Dr. Yun Yen, Department of Molecular Pharmacology, City of Hope,
Arnold & Mabel Beckman Center Building, 1500 East Duarte Blvd, Duarte, CA 91010, USA.
TEL: 626-256-4673 (ext. 65707). E-MAIL:
yyen@coh.org



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