The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene

The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene

Departments of ^*Cancer Genetics, ^†Biochemistry, ^‡Clinical Cytogenetics, and ^**Pediatrics, Roswell Park Cancer Institute, Buffalo, NY 14263; ^§Division of Hematology/Oncology, Miami Children's Hospital, Miami, FL 33155; ^¶Department of Human Genetics, University of Alabama, Birmingham, AL 35294; and ^‖Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892

Edited by Janet D. Rowley, The University of Chicago Medical Center, Chicago, IL, and approved January 4, 2000 (received for review August 4, 1999)

Abstract

We have cloned the genomic breakpoints for a balanced t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia. Sequence analysis of the genomic breakpoints indicated that the translocation had been mediated by an illegitimate V(D)J recombination event that disrupted the T-cell receptor (TCR) α locus and placed the TCR α locus enhancer on the derivative 21 chromosome. We identified a previously unreported transcript, designated BHLHB1 (for basic domain, helix–loop–helix protein, class B, 1) that had been activated by the translocation. BHLHB1 mapped to the region of chromosome 21 that has been proposed to be responsible, at least in part, for the learning deficits seen in children with Down's syndrome. Although BHLHB1 expression normally is restricted to neural tissues, T-cell lymphoblasts with the t(14;21)(q11.2;q22) also expressed high levels of BHLHB1 mRNA. Expression of BHLHB1 dramatically inhibited E2A-mediated transcription activation in NIH 3T3 fibroblasts and Jurkat T cells. This observation suggests that BHLHB1, similar to SCL/TAL1, may exert a leukemogenic effect through a functional inactivation of E2A or related proteins.

Footnotes

↵ ‡‡ To whom reprint requests should be sent at present address: National Cancer Institute, Division of Clinical Sciences, Advanced Technology Center, 8717 Grovemont Circle, Gaithersburg, MD 20877. E-mail: aplanp{at}mail.nih.gov.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF221520).
Abbreviations:

ALL,

acute lymphoblastic leukemia;

T-ALL,

T-cell ALL;

TCR,

T-cell receptor;

RT-PCR,

reverse transcriptase–PCR;

PAC,

P1-artificial chromosome;

CAT,

chloramphenicol acetyltransferase;

EST,

expressed sequence tag;

bHLH,

basic domain helix–loop–helix