Chromosomal change during 6-mercaptopurine (6-MP) therapy in juvenile myelomonocytic leukemia: the growth of a 6-MP-refractory clone that already exists at onset.
Among 11 JMML children, two had an abnormal karyotype, and nine had a normal karyotype at onset. In one patient with trisomy 8 and four patients with a normal karyotype, a new clone with an aberrant karyotype emerged 1-14 months after 6-mercaptopurine (6-MP) therapy as shown by G-banding analyses. Fluorescence in situ hybridization disclosed that an abnormal clone existed in approximately 3-6% of bone marrow cells at onset or before 6-MP therapy in all the four cases examined, and increased to approximately 12-90% during the treatment. In culture with granulocyte-macrophage colony-stimulating factor, cytogenetically abnormal clones that proliferated during 6-MP therapy possessed significantly less sensitivity to the antimetabolite, compared with cells that decreased in numbers after the therapy. A PTPN11 mutation was detected in all of granulocyte-macrophage colonies irrespective of karyotypic aberration in one patient, whereas approximately 80% of erythroid colonies and 20% of mixed colonies possessed neither a PTPN11 mutation nor chromosomal abnormalities. The appearance of chromosomal aberrations shown by G-banding during 6-MP therapy in some JMML cases may result, in part, from the growth of a 6-MP-refractory clone that already exists at onset. It is possible that treatment with 6-MP promotes progression of the disease.
Matsuda
K
K
Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
Matsuzaki
S
S
Miki
J
J
Hidaka
E
E
Yanagisawa
R
R
Nakazawa
Y
Y
Sakashita
K
K
Kamijo
T
T
Asami
K
K
Sano
K
K
Koike
K
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015122:Mercaptopurine / Q000627:therapeutic use*; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D015122:Mercaptopurine; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases