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Different molecular consequences of the 1;19 chromosomal translocation in childhood B-cell precursor acute lymphoblastic leukemia

Privitera, Enrica and Kamps, Mark P. and Hayashi, Yasuhide and Inaba, Toshiya and Shapiro, Linda H. and Raimondi, Susana C. and Behm, Frederic and Hendershot, Linda and Carroll, Andrew J. and Baltimore, David and Look, A. Thomas (1992) Different molecular consequences of the 1;19 chromosomal translocation in childhood B-cell precursor acute lymphoblastic leukemia. Blood, 79 (7). pp. 1781-1788. ISSN 0006-4971. http://resolver.caltech.edu/CaltechAUTHORS:20120328-134128939

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://bloodjournal.hematologylibrary.org/content/79/7/1781PublisherUNSPECIFIED
Additional Information:© 1992 by The American Society of Hematology. Submitted July 26, 1991; accepted November 20, 1991. Supported in part by Grants CA-20180, CA-42804, CA-21765, CA-30969, CA-51462, and GM-43576 from the National Institutes of Health, and by the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children's Research Hospital. M.P.K. is supported by the Damon Runyon-Walter Winchell Cancer Research Fund, Grant DRF982. We are indebted to Geoffrey Kitchingman for assistance with leukemia cell DNA samples, to Cornelis Murre for providing the pE47M cDNA probe, to Kevin Coleman, Pam Freiden, Bart Jones, Elizabeth Mann, Anne Sinclair, Rose Anne Lambert, and Kent Williams for expert technical assistance, and to John Gilbert for editorial assistance and critical comments.
Funders:
Funding AgencyGrant Number
NIHCA-20180
NIHCA-42804
NIH CA-21765
NIHCA-30969
NIHCA-51462
NIHGM-43576
St Jude Children's Research Hospital American Lebanese Syrian Associated Charities (ALSAC)UNSPECIFIED
Damon Runyon-Walter Winchell Cancer Research FundDRF982
Record Number:CaltechAUTHORS:20120328-134128939
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120328-134128939
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29882
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Apr 2012 23:24
Last Modified:26 Dec 2012 15:00

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