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The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials

Kamps, Mark P. and Look, A. Thomas and Baltimore, David (1991) The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes and Development, 5 (3). pp. 358-368. ISSN 0890-9369. doi:10.1101/gad.5.3.358. https://resolver.caltech.edu/CaltechAUTHORS:20200518-073943504

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Abstract

The t(1;19) translocation that characterizes 25% of pediatric pre-B cell acute lymphoblastic leukemias (pre-B ALL) produces a chimeric gene, joining 5' sequences that encode a transcriptional activator domain of E2A with 3' sequences that, in part, encode a homeo box domain of a new gene called pbx1. Two E2A-pbx1 transcripts have been cloned. They encode the putative fusion proteins, p85^(E2A-Pbx1) and p77^(E2A-Pbx1), which differ in Pbx1 sequences alone, containing unique carboxyl termini whose sequences diverge after the Pbx1 homeo box. In this study, an antiserum to Pbx1 was used to investigate the identity and abundance of E2A-Pbx1 fusion proteins in both the pre-B ALL cell line, 697, and in cryopreserved leukemic bone marrow cells, obtained from six children with t(1;19)-positive pre-B ALL. Five species of E2A-Pbx1 proteins were identified in all cells containing t(1;19), two of which were indistinguishable from in vitro-translated p85^(E2A-Pbx1) and p77^(E2A-Pbx1). To assess the biological properties of p85^(E2A-Pbx1) and p77^(E2A-Pbx1) in fibroblasts, the cDNAs encoding these proteins were cloned into retroviral vectors, and each was introduced into NIH-3T3 cells. Both p85^(E2A-Pbx1) and p77^(E2A-Pbx1) are localized in the nucleus, and expression of either resulted in malignant conversion of NIH-3T3 cells as assayed by tumor formation in nude mice. When scored by focus formation, density-independent growth, and growth in agar assays, p77^(E2A-Pbx1) was a much more potent transforming protein than was p85^(E2A-Pbx1). Because subtle mutations in p85^(E2A-Pbx1) converted its transforming activity into that of p77^(E2A-Pbx1), we suggest that a sequence within the unique carboxyl terminus of p85^(E2A-Pbx1) serves to negatively regulate its biochemical activity.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/gad.5.3.358DOIArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 1991 by Cold Spring Harbor Laboratory. Received July 18, 1990; revised version accepted January 14, 1991. We thank Comelis Murre and Sybille Mittnacht for their generous gifts of antisera to E2A and Rb, respectively. We alsothank Susana Raimondi for expert cytogenetic analysis of leukemic lymphoblasts. M.P.K. is supported by a Damon Runyon-Walter Winchell Cancer Research Fund Fellowship, DRG-982. This work was supported by National Institutes of Health grant GM39458 and by grants CA-42804, CA-20180, and CA-21765 and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
Damon Runyon Cancer Research FoundationDRG-982
NIHGM39458
NIHCA-42804
NIHCA-20180
NIHCA-21765
St. Jude Children's Research HospitalUNSPECIFIED
Subject Keywords:t(1;19) translocation; pre-B ALL; homeo box domain; nuclear fusion proteins
Issue or Number:3
DOI:10.1101/gad.5.3.358
Record Number:CaltechAUTHORS:20200518-073943504
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200518-073943504
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103258
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 May 2020 16:01
Last Modified:16 Nov 2021 18:19

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