Abstract
AbstractBCR-ABL kinase domain (KD) mutations, the most common cause of imatinib resistance, are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) patients. Recent studies indicate pre-existing mutations (PEMs) can be detected in a higher percentage of CML patients using CD34+ stem/progenitor cells, and these mutations may correlate with imatinib resistance. We investigated KD mutations in CD34+ stem cells from 100 CP-CML patients by multiplex ASO-PCR and sequencing ASO-PCR products at the time of diagnosis. PEMs were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48), all patients with PEMs exhibited imatinib resistance. Of 68 patients without PEMs, 24 developed imatinib resistance. Mutations were detected in 21 of these patients by ASO-PCR and KD sequencing. All 32 patients with PEMs had the same mutations. In imatinib-resistant patients without PEMs, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients without T315I and Y253F mutations responded to imatinib dose escalation. In conclusion, BCR-ABL PEMs can be detected in a substantial number of CP-CML patients when investigated using CD34+ stem/progenitor cells. These mutations are associated with imatinib resistance, and mutation testing using CD34+ cells may facilitate improved, patient-tailored treatment.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the t(9;22) chromosomal translocation
Namely T315I, F311L, and M351T, either alone or in combination, as pre-existing mutations (PEMs) in this group of CML patients
The BCR-ABL fusion gene is highly unstable in these primitive CML cells, and it is associated with frequent genetic alterations and mutations in BCR-ABL itself as well as in other genes such as p53 even in the absence of imatinib exposure 34
Summary
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the t(9;22) chromosomal translocation. This translocation results in the formation of BCR-ABL fusion gene, which is central to the pathogenesis of CML. A tyrosine kinase inhibitor (TKI), induces durable responses in the majority of CML patients and is currently the standard of care for CML 2, 3. The presence of KD mutations has been studied mostly in the advanced phase of CML (accelerated phase and blast crisis), in chronic phase (CP) patients who develop resistance to imatinib, and in Philadelphia-positive (Ph+) acute lymphoblastic leukemia [5, 10,11,12,13]
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