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Generation and Application of a Transgenic Model for Chronic Myelogenous Leukemia

Issue: Vol.10, No.3 - July 2011

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Article Type: Manuscript

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  1. Dr Hiroaki Honda
    Department of Disease Model, Research Institute of Radiation Biology and Medicine,
    Hiroshima University,

Chronic myelogenous leukemia (CML) is a hematopoietic disorder, characterized by excessive and uncontrolled proliferation of myeloid cells with differentiation ability. CML
originates from hematopoietic stem cells transformed by p210BCR/ABL, a chimeric protein with enhanced tyrosine kinase activity. Clinically, CML begins as an indolent phase, called chronic phase (CP), where the tumor cells retain the ability to differentiate into mature granulocytes. However, it inevitably accelerates and progresses to a fatal phase, called blast crisis (BC), where immature blast cells aggressively proliferate. The transition from CP to BC is considered to be caused by secondary genetic events, but precise molecular mechanisms underlying disease evolution have remained unclear. To understand the complex disease processes of CML, it is necessary to establish an animal model that expresses p210BCR/ABL and recapitulates the clinical course of the disease. To address this issue, I cloned a promoter region of a gene preferentially expressed in hematopoietic stem/progenitor cells and generated transgenic mice expressing p210BCR/ABL under the control of the promoter. The transgenic progeny reproducibly exhibited cardinal features of CML CP, indicating the transgenic mice to be a novel animal model for human CML. This shows the first success of creating a CML model by a transgenic approach and also the first stable and hereditary model for CML. Using the transgenic mice, I analyzed the pathogenic mechanism for initiating CML CP and identified secondary gene alterations responsible for the transition from CP to BC.

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