Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy
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Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy Mohamed A. M. Ali1
Ó Springer International Publishing Switzerland 2016
Abstract Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q? and a shortened 22q–. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCRABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms—either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling—have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for & Mohamed A. M. Ali [email protected] 1
Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt
diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and independent mechanisms that contribute to the development of resistance to TKIs.
Key Points Chronic myeloid leukemia (CML) represents a model disorder for the principle of cancer molecularly targeted therapy. The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved the clinical outcome of CML and revolutionized CML management. About one-third of newly diagnosed CML patients do not respond optimally to first-line TKI therapy, because of either primary or secondary resistance or intolerance.
1 Introduction Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a consistent chromosomal abnormality—the t(9; 22) chromosomal translocation, which generates the Philadelphia (Ph) chromosome [1]. The resulting breakpoint cluster region-abelson (BCRABL) oncogenic fusion gene, encoding a constitutively active fusion tyrosine kinase, has been shown to be necessary and sufficient for the transformed phenotype of CML cells [2].
M. A. M. Ali
The in
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