A 60-year-old man who was recently retired has been devoting a great deal to tim

A 60-year-old man who was recently retired has been devoting a great deal to time playing tennis in the past year. He has observed increasing fatigue in the past three months and presently unable to finish a meal despite his voracious appetite. He became quite concerned and wondered what this change in body physiology means. He schedules an appointment with the doctor for medical evaluation and on physical examination the doctor noted an enlarged spleen that extended approximately 10 cm below the left coastal margin but withing normal limits. The clinical parameters show an increase in total white blood cell counts (70,000 cell/mm3) with an absolute increase in neutrophils, band forms, metamyelocytes and myelocytes but there were no blast cells (undifferentiated precursor cells). Cytogenetic analysis of metaphase cells demonstrates that 90% of his myeloid cells possess the Philadelphia chromosomes (indicating a translocation between chromosome 9 and 22), confirming the diagnosis of chronic myeloid leukemia. Therapeutic intervention was initiated, and the Physician placed him on imatinib, a highly selective inhibitor of the BCR-Abl tyrosine kinase fusion protein that is encoded by the Philadelphia chromosome. Over the next month, the cells containing the Philadelphia chromosomes disappeared completely from the man blood and he begins to feel well enough to compete in a senior tennis tournament. The man continues to take the drug (imatinib) every day, and he has a completely normal blood and no fatigue. He is not sure what the future will bring but he is glad to have given the chance to enjoy a healthy retirement.
Instructions
1. How does imatinib interrupt the activity of the BCR-Abl tyrosine kinase fusion protein?
2. Unlike imatinib, most of the older therapies for chronic myeloid leukemia (such as interferon-α) had significant “flu like” adverse effects. Why did these therapies cause significant adverse effects in most patients, whereas (as in this case) causes adverse effects in very few patients?
3. Why is imatinib a selective therapy for chronic myeloid leukemia? In this selectivity related to the lack of adverse effects associated with imatinib therapy?
4. How does the BCR-Abl protein affect intracellular signaling pathways?