BCR-ABL gene amplification and overexpression in a patient with chronic myeloid leukemia treated with imatinib.
Imatinib mesylate was designed as an inhibitor targeting the BCR-ABL tyrosine kinase, the molecular counterpart of the Philadelphia translocation t(9;22)(q34;q11). We report on a patient with chronic myeloid leukemia (CML) undergoing acceleration during imatinib treatment. Cytogenetic analysis revealed four different cell populations: 46,XX,t(9;22)(q34;q11),der(18)t(2;18)(p11;p11)[1]/47,idem,i(17)(q10),-der(18)t(2;18),+der(22)t(9;22)[1]/46,idem,-t(9;22),der(9)t(9;22),ider(22)t(9;22)[12]/ 47,idem,-t(9;22),der(9)t(9;22),+22,ider(22)t(9;22)x2[1]. FISH analysis confirmed the presence of these four clones. Moreover, 49% of the interphase nuclei contained either one or two clustered fusion signals, indicating a low-level amplification of the BCR-ABL fusion gene. With quantitative real-time RT-PCR, a BCR-ABL/G6PDH ratio of 0.8 was determined, which is comparable to that measured in the K562 cell line with a known BCR-ABL amplification and which is increased by more than about 60-fold compared to a CML at diagnosis with >80% Philadelphia-positive cells. We give further evidence that the genomic BCR-ABL amplification results in an increased level of BCR-ABL transcript linking two potent mechanisms of resistance against imatinib treatment.
Gadzicki
Dorothea
D
Institute of Cell and Molecular Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
von Neuhoff
Nils
N
Steinemann
Doris
D
Just
Marianne
M
Büsche
Guntram
G
Kreipe
Hans
H
Wilkens
Ludwig
L
Schlegelberger
Brigitte
B
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000627:therapeutic use; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; C015482:protein kinase modulator; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl