Evidence of ABL-kinase domain mutations in highly purified primitive stem cell populations of patients with chronic myelogenous leukemia.
To study the hierarchical levels of stem cell targets for ABL-kinase domain mutations in CML, highly purified CD34+CD38- and CD34+CD38+ cell populations and their LTC-IC-derived progeny were analyzed in four patients at diagnosis (n=1) or in advanced phases (n=3) of their disease. In the single patient with early phase CML who later developed an Imatinib Mesylate-resistance and a Y253H mutation, no mutation was detectable in purified cell fractions analyzed at diagnosis nor in their LTC-IC-derived progeny. In contrast, in three patients in advanced phase CML, ABL-kinase mutations demonstrated in peripheral blood cells by sequencing (Q252E and M351T) were detectable in the FACS-sorted cells and became amplified in the LTC-IC-derived progeny of the primitive cells. These findings demonstrate that in late CP or advanced CML, ABL-kinase mutations occur as an intraclonal event in the primitive Ph1+ stem cell compartments with progression of this clone towards IM-resistant blast phase.
Sorel
N
N
Laboratory of Hematology, Hôpital de la Miletrie, CHU Poitiers, France.
Bonnet
M L
ML
Guillier
M
M
Guilhot
F
F
Brizard
A
A
Turhan
A G
AG
D000970:Antineoplastic Agents / Q000008:administration & dosage; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000008:administration & dosage*; D020539:Sequence Analysis, Protein; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010770:Phosphotransferases; D016044:Fusion Proteins, bcr-abl