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Different molecular consequences of the 1;19 chromosomal translocation in
childhood B-cell precursor acute lymphoblastic leukemia
E Privitera, MP Kamps, Y Hayashi, T Inaba, LH Shapiro, SC Raimondi, F Behm, L Hendershot, AJ Carroll and D Baltimore
Department of Hematology-Oncology, St Jude Children's Research Hospital,
Memphis, TN 38105.
The prognostically important 1;19 chromosomal translocation can alter the
E2A gene on chromosome 19p13 in childhood B-cell precursor acute
lymphoblastic leukemia (ALL), leading to formation of a fusion gene
(E2A-PBX1) that encodes a hybrid transcription factor with oncogenic
potential. It is not known whether this molecular alteration is a uniform
consequence of the t(1;19) or is restricted to translocation events within
specific immunologic subtypes of the disease. Therefore, we studied
leukemic cells from 25 cases of B-cell precursor ALL, with or without
evidence of cytoplasmic Ig mu heavy chains (cIg); 17 cases had the t(1;19)
by cytogenetic analysis. Leukemic cell DNA samples were analyzed by
Southern blotting to detect alterations within the E2A genomic locus; a
polymerase chain reaction assay was used to identify expression of chimeric
E2A-pbx1 transcripts in leukemic cell RNA; and immunoblotting with
anti-Pbx1 antibodies was used to detect hybrid E2A- Pbx1 proteins. Of 11
cases of cIg+ ALL with the t(1;19), 10 had E2A- pbx1 chimeric transcripts
with identical junctions and a characteristic set of E2A-Pbx1 hybrid
proteins. Each of these cases had E2A gene rearrangements, including the
one in which fusion transcripts were not detected. By contrast, none of the
six cases of t(1;19)-positive, cIg- ALL had evidence of rearranged E2A
genomic restriction fragments, detectable E2A-pbx1 chimeric transcripts, or
hybrid E2A-Pbx1 proteins. Typical chimeric E2A-pbx1 transcripts and
proteins were detected in one of eight cIg+ leukemias in which the t(1;19)
was not identified by cytogenetic analysis, emphasizing the increased
sensitivity of molecular analysis for detection of this abnormality. We
conclude that the molecular breakpoints in cases of cIg- B-cell precursor
ALL with the t(1;19) differ from those in cIg+ cases with this
translocation. Leukemias that express hybrid oncoproteins such as E2A-Pbx1
or Bcr-Abl have had a poor prognosis in most studies. Thus, molecular
techniques to detect fusion genes and their aberrant products should allow
more timely and appropriate treatment of these aggressive subtypes of the
disease.
Volume 79,
Issue 7,
pp. 1781-1788,
04/01/1992
Copyright © 1992 by The American Society of Hematology
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