Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment.
T315I mutation of the ABL-kinase domain in chronic myeloid leukemia (CML) confers resistance to imatinib (IM) as well as second-generation tyrosine kinase inhibitors (TKIs). We report a chronic-phase CML patient undergoing IM treatment, who showed the overt existence of the T315I mutation after 15 months. We retrospectively analyzed the distribution of the T315I mutation using the invader assay and direct DNA sequencing among FACSAria-sorted populations from bone marrow cells: total mononuclear cells (TMC), hematopoietic stem cells (HSC)/Thy-1(+), HSC/Thy-1⁻, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythroid progenitors (MEP), at 0, 3, 6, 9, and 12 months after IM treatment. T315I was barely detectable by 12 months in TMC, but detectable in 19.2% of HSC/Thy-1⁻ and 46.4% of MEP at diagnosis, and finally expanded into all populations. These results suggest that the monitoring of gene mutations in HSC and progenitors at diagnosis might be helpful for the early detection of TKI-resistant CML patients and facilitate appropriate therapeutic decision.
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. yminami@med.nagoya-u.ac.jp
Yosuke
Y
Minami
Tomohiro
T
Kajiguchi
Akihiro
A
Abe
Toshihito
T
Ohno
Hitoshi
H
Kiyoi
Tomoki
T
Naoe
D000328:Adult; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001854:Bone Marrow Cells; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry; D016313:Genes, abl / Q000235:genetics*; D006412:Hematopoietic Stem Cells; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012189:Retrospective Studies
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl