Role of Imatinib-Sensitive Tyrosine Kinases in the Pathogenesis of Chronic Myeloproliferative Disorders

Myelodysplastic syndromes (MDSs) and myeloproliferative disorders (MPDs) are clonal diseases that affect hematopoietic stem cells and progenitor cells within the erythroid, megakaryocytic, and granulocytic lineages. Blood cells from patients with MDS exhibit an excess rate of blast divisions, a high rate of dysplasia, and increased apoptosis. Patients with MPDs exhibit predominant proliferation of one cell lineage within the marrow. The World Health Organization (WHO) developed a new classification system for malignant hematologic conditions that includes a hybrid category referred to as MDS/MPD that takes into consideration dysplastic and proliferative characteristics. The new MDS/MPD category includes three clonal MPDs: atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), and juvenile myelomonocytic leukemia (JMML). The prognosis for patients with clonal MPDs varies depending on severity but is usually considerably shorter than for patients with CML because these diseases are refractory to treatment. These hematologic disorders can be associated with chromosomal translocations that involve genes encoding protein kinases. Constitutive kinase activity of the resulting fusion protein is the underling mechanism of oncogenesis. Examples in which fusion protein kinase activity is sensitive to imatinib provide the rationale for targeted therapy with the drug. Treatment with imatinib of patients with clonal MPDs carrying ABL, platelet-derived growth factor receptor alpha (PDGFRα), or PDGFRβ fusion kinases has resulted in significant hematologic and cytogenetic remissions. Therefore, diagnosis of clonal MPDs should include cytogenetic and molecular screening for therapeutically relevant chromosomal rearrangements involving imatinib-sensitive targets.