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Involvement of the CEBP gene family in four IGH@ chromosomal translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

Involvement of the CEBP gene family in four IGH@ chromosomal translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
Involvement of the CEBP gene family in four IGH@ chromosomal translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are rare in BCP-ALL (comprising ~3% of cases) and involve different breakpoints from those found in lymphoma and myeloma. Cytogenetics, metaphase and interphase FISH, using a split-signal probe specific for IGH@, identified four translocations: t(14;19)(q32;q13) (n = 10), t(8;14)(q11;q32) (n = 8), t(14;14)(q11;q32) (n =3) and t(14;20)(q32;q13) (n=2), among a series of BCP-ALL patients. Sequential FISH mapping of these translocations showed that four different members of the CEBP gene family flanked these breakpoint regions. Long-distance inverse PCR with primers specific for the IGHJ6 gene segment allowed molecular cloning of many of these breakpoints and confirmed the involvement of the CEBPA (19q13, n= 4), CEBPD (8q11, n=6), CEBPE (14q11, n =2) genes. Breakpoints were located within the 3' UTR of CEBPA and either 3' UTR or the 5' region of CEBPE, whereas breakpoints in 8q11 were ~30kb centromeric of CEBPD. Over-expression of the respective target genes was shown by QRT-PCR. Evidence that the IGH@ locus directly contributed to gene deregulation was demonstrated by lower expression of CEBPA in 9/17 derived BCP-ALL cell lines without t(14;19)(q32;q13). CEBP proteins have been implicated in the differentiation of myeloid progenitors and CEBPA mutations have been detected in a subset of sporadic and familial acute myeloid leukemia, suggesting that CEBPA may act as a tumor suppressor gene in these malignancies. However, no mutations within the 5' region of CEBPA comparable to those seen in AML were detected in any cases with t(14;19)(q32;q13), although one case did exhibit deletion of six nucleotides resulting in the loss of 2 amino acids. Moreover, the deregulated expression of CEBPA and other CEBP genes in a subset of BCP-ALL indicates that they may act as dominant oncogenes in B-cell precursors. Constitutive expression of CEBPA and CEBPB in normal lymphoid progenitors has previously been shown to induce myeloid differentiation whilst CEBPE is involved in the terminal differentiation of neutrophils. We showed that expression of full-length CEBPE in the IL3-dependent B-cell precursor cell line Ba/F3 did not result in enhanced proliferation or protection from a variety of apoptotic stimuli, but instead resulted in expression of myeloid differentiation antigens. Most CEBP genes are intronless, different protein isoforms with differing functions being generated translationally. 2-D western blot analysis of nuclear extracts from the SEM BCP-ALL cell line showed selective expression of the 32kd CEBPA protein isoform only, an isoform that lacks the anti-mitotic activity of full-length CEBPA. These data implicate deregulation of the CEBP gene family via juxtaposition to the IGH@ in the pathogenesis of a subset of BCP-ALL. They demonstrate for the first time, the involvement of four members of the same gene family in a single subtype of hematological disease. The transformation of B-cell progenitors may occur through the selective expression of shorter CEBP protein isoforms that lack the ability to induce myeloid differentiation.
chromosomal translocation, gene, translocation, b cell, families, acute lymphoblastic leukemia, time, leukemia
0006-4971
p.797A
Dyer, Martin J.S.
1adc9629-1d82-4ede-83a4-15d4afd67b35
Akasaka, Takashi
e9ed8fda-8291-42e9-84b1-c598d222197c
Balasas, Theodore
edc71c45-7a74-4cd0-b93c-10f52bf1986c
Russell, Lisa
a0472729-08df-4ac1-88d4-56dfdf3952d1
Sugimoto, Kei-Ji
59b6214d-1977-4390-b81c-98ae18292753
Majid, Aneela
0e54cc85-a5ec-490f-b796-f6dd7d2c4881
Brown, David G.
83f5d2bf-965a-47f3-93a8-259bc15bb0ce
Cain, Kelvin
920ed2c7-42e2-4d99-b1c0-ccf269778bb5
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Siebert, Reiner
47869d4a-d35d-4638-8744-1adb6e03fadb
Dyer, Martin J.S.
1adc9629-1d82-4ede-83a4-15d4afd67b35
Akasaka, Takashi
e9ed8fda-8291-42e9-84b1-c598d222197c
Balasas, Theodore
edc71c45-7a74-4cd0-b93c-10f52bf1986c
Russell, Lisa
a0472729-08df-4ac1-88d4-56dfdf3952d1
Sugimoto, Kei-Ji
59b6214d-1977-4390-b81c-98ae18292753
Majid, Aneela
0e54cc85-a5ec-490f-b796-f6dd7d2c4881
Brown, David G.
83f5d2bf-965a-47f3-93a8-259bc15bb0ce
Cain, Kelvin
920ed2c7-42e2-4d99-b1c0-ccf269778bb5
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Siebert, Reiner
47869d4a-d35d-4638-8744-1adb6e03fadb

Dyer, Martin J.S., Akasaka, Takashi, Balasas, Theodore, Russell, Lisa, Sugimoto, Kei-Ji, Majid, Aneela, Brown, David G., Cain, Kelvin, Strefford, Jon C., Harrison, Christine J. and Siebert, Reiner (2005) Involvement of the CEBP gene family in four IGH@ chromosomal translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood, 106 (11), p.797A.

Record type: Article

Abstract

Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are rare in BCP-ALL (comprising ~3% of cases) and involve different breakpoints from those found in lymphoma and myeloma. Cytogenetics, metaphase and interphase FISH, using a split-signal probe specific for IGH@, identified four translocations: t(14;19)(q32;q13) (n = 10), t(8;14)(q11;q32) (n = 8), t(14;14)(q11;q32) (n =3) and t(14;20)(q32;q13) (n=2), among a series of BCP-ALL patients. Sequential FISH mapping of these translocations showed that four different members of the CEBP gene family flanked these breakpoint regions. Long-distance inverse PCR with primers specific for the IGHJ6 gene segment allowed molecular cloning of many of these breakpoints and confirmed the involvement of the CEBPA (19q13, n= 4), CEBPD (8q11, n=6), CEBPE (14q11, n =2) genes. Breakpoints were located within the 3' UTR of CEBPA and either 3' UTR or the 5' region of CEBPE, whereas breakpoints in 8q11 were ~30kb centromeric of CEBPD. Over-expression of the respective target genes was shown by QRT-PCR. Evidence that the IGH@ locus directly contributed to gene deregulation was demonstrated by lower expression of CEBPA in 9/17 derived BCP-ALL cell lines without t(14;19)(q32;q13). CEBP proteins have been implicated in the differentiation of myeloid progenitors and CEBPA mutations have been detected in a subset of sporadic and familial acute myeloid leukemia, suggesting that CEBPA may act as a tumor suppressor gene in these malignancies. However, no mutations within the 5' region of CEBPA comparable to those seen in AML were detected in any cases with t(14;19)(q32;q13), although one case did exhibit deletion of six nucleotides resulting in the loss of 2 amino acids. Moreover, the deregulated expression of CEBPA and other CEBP genes in a subset of BCP-ALL indicates that they may act as dominant oncogenes in B-cell precursors. Constitutive expression of CEBPA and CEBPB in normal lymphoid progenitors has previously been shown to induce myeloid differentiation whilst CEBPE is involved in the terminal differentiation of neutrophils. We showed that expression of full-length CEBPE in the IL3-dependent B-cell precursor cell line Ba/F3 did not result in enhanced proliferation or protection from a variety of apoptotic stimuli, but instead resulted in expression of myeloid differentiation antigens. Most CEBP genes are intronless, different protein isoforms with differing functions being generated translationally. 2-D western blot analysis of nuclear extracts from the SEM BCP-ALL cell line showed selective expression of the 32kd CEBPA protein isoform only, an isoform that lacks the anti-mitotic activity of full-length CEBPA. These data implicate deregulation of the CEBP gene family via juxtaposition to the IGH@ in the pathogenesis of a subset of BCP-ALL. They demonstrate for the first time, the involvement of four members of the same gene family in a single subtype of hematological disease. The transformation of B-cell progenitors may occur through the selective expression of shorter CEBP protein isoforms that lack the ability to induce myeloid differentiation.

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More information

Published date: 16 November 2005
Additional Information: ASH Annual Meeting Abstracts, Poster Sessions. Abstract 2842.
Keywords: chromosomal translocation, gene, translocation, b cell, families, acute lymphoblastic leukemia, time, leukemia

Identifiers

Local EPrints ID: 62726
URI: http://eprints.soton.ac.uk/id/eprint/62726
ISSN: 0006-4971
PURE UUID: 6dba0b03-0ea7-43f7-9c4f-a88669c188db
ORCID for Jon C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 11 Nov 2008
Last modified: 23 Jul 2022 01:53

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Contributors

Author: Martin J.S. Dyer
Author: Takashi Akasaka
Author: Theodore Balasas
Author: Lisa Russell
Author: Kei-Ji Sugimoto
Author: Aneela Majid
Author: David G. Brown
Author: Kelvin Cain
Author: Christine J. Harrison
Author: Reiner Siebert

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