title: Analysis of mutations in the BCR-ABL1 kinase domain, using direct sequencing: detection of the T315I mutation in bone marrow CD34+ cells of a patient with chronic myelogenous leukemia 6 months prior to its emergence in peripheral blood.
abstract: OBJECTIVE
  It has been shown that the occurrence of the BCR-ABL1 T315I mutation leads to a very poor therapeutic outcome in chronic myelogenous leukemia (CML) patients treated with tyrosine kinase inhibitors. Therefore, early detection of this mutation could potentially lead to early therapeutic intervention and a better prognosis with the ongoing treatment regimen.
  
  
  METHODS
  The detection of BCR-ABL1 kinase domain (KD) mutations was performed by direct sequencing of peripheral blood (PB), total bone marrow (BM), and BM CD34+ cells from a reported CML patient.
  
  
  RESULTS
  In this patient, the T315I mutation was detected in BM CD34+ cells 6 months prior to its emergence in PB, suggesting evolution and expansion of the T315I mutation clone, which most likely originated from more primitive CML cells.
  
  
  CONCLUSIONS
  Our finding reflects the natural development of a T315I mutation within the hematopoietic system of the reported patient and indicates the importance of BCR-ABL1 mutation monitoring in more primitive cell populations. Considering the natural history of T315I development in this reported CML case, we hypothesize that BCR-ABL1 KD mutations may be pre-concentrated in more primitive CML cells, which subsequently expand into the PB. These findings may have future implications for the strategy used for detecting BCR-ABL1 mutations.
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: Filip
authors.initials: F
authors.lastname: Razga
authors.forename: Tomas
authors.initials: T
authors.lastname: Jurcek
authors.forename: Ivana
authors.initials: I
authors.lastname: Jeziskova
authors.forename: Daniela
authors.initials: D
authors.lastname: Zackova
authors.forename: Dana
authors.initials: D
authors.lastname: Dvorakova
authors.forename: Marek
authors.initials: M
authors.lastname: Borsky
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Racil
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology*; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D006918:Hydroxyurea