Clonal instability preceding lymphoid blastic transformation of chronic myeloid leukemia.
We have sought the presence of rearrangements of the immunoglobulin heavy chain gene locus in 13 patients with chronic myeloid leukemia (CML) in lymphoid blastic transformation (L-BT) using the polymerase chain reaction (PCR). The lymphoid nature of the transformation was confirmed by immunophenotyping and/or Southern blot hybridization with a J(H) probe. Clonal rearrangements were detected in 85% of cases and two or more rearrangements were visible in 64% of informative cases. The pattern of V(H) gene family utilization revealed an apparent reduction in V(H)4 family gene usage but otherwise reflected the known proportion of each gene family in the germline repertoire. In six cases the third complementary determining regions (CDR3) of the predominant blast crisis clone/s were sequenced revealing minimal evidence of somatic mutation. No clonal changes were detected in the chronic phase leukemia cells collected more than 6 months before the onset of L-BT in three of these patients. Of the other three patients studied in chronic phase from 1 to 6 months before L-BT, two showed clonal rearrangements which differed in size from those present at L-BT. In one patient a V(H)3 to V(H)5-D(H)-J(H) substitution had occurred at least 3 months prior to L-BT. In the other patient, however, the sequence of the rearrangement present 5 months prior to L-BT was unrelated to the rearrangements at the time of L-BT indicating a pattern of clonal succession. We conclude that: (1) IgH gene rearrangements are detectable in the majority of patients with L-BT using PCR and the lymphoid lineage of blastic CML is most readily confirmed using consensus primers to the framework 3 region; (2) somatic mutation is uncommon; and (3) B lymphoid clones distinct from those identified later may be detected before overt lymphoid BT. The identification of such 'abortive' clones is evidence for clonal instability before the onset of transformation and might have prognostic value.
Spencer
A
A
Haematology Unit, Mater Hospital, Newcastle, NSW, Australia.
Vulliamy
T
T
Kaeda
J
J
Goldman
J M
JM
Melo
J V
JV
D000293:Adolescent; D000328:Adult; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology*; D001773:Blood Cells / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology; D002999:Clone Cells / Q000473:pathology*; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins