t(14;19)(q32;q13) IGH/CEBPA

2008-05-01 Jean-Loup Huret Affiliation

1.Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France
2.Leukaemia Research Fund Cytogenetics Group, Cancer Sciences Division, University of Southampton, MP 822, Duthie Building, Southampton General Hospital, Southampton, SO16 6YD, UK

Clinics and Pathology

Disease

Acute lymphoblastic leukaemia (ALL)

Phenotype stem cell origin

B-lineage immunophenotype and FAB L1, mostly CD10+ : B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Epidemiology

Rare, with only 28 cases reported to date (Heerema et al., 1985; Prigogina et al., 1988; Pui et al., 1993; Andreasson et al., 2000; Robinson et al., 2004; Chapiro et al., 2006; Akasaka et al., 2007). The estimated incidence in childhood and adult ALL is

Clinics

Typically, patients with this abnormality have low white cell count of

Prognosis

It is difficult to assess the true prognosis of patients with this abnormality given its rarity, however initial data suggest that the prognosis is better than expected for patients of a similar age (see Figure 2).

Cytogenetics

Note

This balanced translocation can usually be identified by G-banding alone. The breakpoint on chromosome 14 is consistently given as 14q32; however the breakpoint on chromosome 19 has, in the past, been more variably attributed, from q11 to q13. It is to be noted, however, that the gene involved on chromosome 19, CEBPA, lies at 38,482,776 bp from pter, very close to the q12 band limit.

Cytogenetics morphological

The t(14;19) has been described as the sole abnormality in 12 out of 28 cases, and is more frequently accompanied by additional structural and/or numerical abnormalities; +21 (acquired) was found in three cases, +6 in two cases. A t(9;22)(q34;q11) was found in one case, a trisomy 8 in one case.
This abnormality has been reported in a single case with Down syndrome. In a closely related translocation, the t(8;14)(q11;q32) with CEBPD/IGH involvement, more than 1/4 of cases were Down syndrome patients.

Genes Involved and Proteins

Note

The involvement of the IGH gene located at 14q32 has been demonstrated via FISH using the LSI IGH Dual Colour Break Apart Rearrangement Probe in all cases tested. Metaphase and interphase FISH using probes flanking the BCL3 gene have ruled out the involved of this gene; thus distinguishing it from the cytogenetically identical translocation t(14;19)(q32;q13) seen in CLL and other chronic B-cell lymphoproliferative disorders.

Gene name

IGH (Immunoglobulin Heavy)

Location

14q32.33

Gene name

CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha)

Location

19q13.1

Note

Alternatively, CEBPG can be involved instead of CEBPA (one case so far described). It is unknown if they bear the same prognosis, as they differ in their N-term.

Dna rna description

CEBPA is a single-exon gene, CEBPG also.

Protein description

DNA-binding protein. CCAAT enhancer-binding protein (CEBP) transcription factors are a family of 6 multifunctional basic leucine zipper (bZIP) transcription factors. The 4 other CEBPs are: CEBPB (20q13), CEBPD (8q11), CEBPE (8q11), all three equally implicated in leukemias, and DDIT3/CHOP/CEBP zeta (12q13), so far known to be involved in solid tumours (liposarcoma). These transcription factors play a key role in cellular differentiation, in particular in the control of myeloid differentiation. CEBPA is composed of a N-term transactivation domain, a negative regulatory domain, a DNA-binding basic motif, and a leucine-zipper domain in C-term. CEBPA mRNA is translated into two major proteins, p42CEBPA and p30CEBPA. The 30 kDa protein lacks the transactivating domain, and inhibits DNA binding and transactivation by p42CEBPA. CEBPA is essential for the lineage specific differentiation of myelocytic haematopoietic precursors into mature neutrophils. CEBPG only contains a DNA-binding basic motif, and a leucine-zipper domain (Ramji et al., 2002; Nerlov et al., 2007).

Germinal mutations

CEBPA has been found mutated in a familial acute myeloid leukemia (Smith et al., 2004).

Somatic mutations

10% of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) cases exhibit a mutation in CEBPA, It seems to bear a good prognosis

Result of the Chromosomal Anomaly

Oncogenesis

Overexpression of the CEBP gene.

Bibliography

Pubmed ID	Last Year	Title	Authors
17170124	2007	Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).	Akasaka T et al
10914938	2000	Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias.	Andreasson P et al
16873674	2006	Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia.	Chapiro E et al
3857967	1985	Karyotypic and clinical findings in a consecutive series of children with acute lymphocytic leukemia.	Heerema NA et al
17658261	2007	The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control.	Nerlov C et al
3163259	1988	Nonrandom chromosomal abnormalities in acute lymphoblastic leukemia of childhood.	Prigogina EL et al
8315434	1993	Immunophenotypes and karyotypes of leukemic cells in children with Down syndrome and acute lymphoblastic leukemia.	Pui CH et al
12006103	2002	CCAAT/enhancer-binding proteins: structure, function and regulation.	Ramji DP et al
14603446	2004	t(14;19)(q32;q13): a recurrent translocation in B-cell precursor acute lymphoblastic leukemia.	Robinson HM et al
15575056	2004	Mutation of CEBPA in familial acute myeloid leukemia.	Smith ML et al

Summary

Mesh

Fusion gene

IGH/CEBPA IGH (14q32.33) CEBPA (19q13.11) M t(14;19)(q32;q13)

Note

This abnormality is cytogenetically identical but molecularly distinct from the t(14;19)(q32;q13) seen in chronic lymphoid leukaemia (CLL) and other chronic B-cell lymphoproliferative disorders, which results in the juxtaposition of BCL3 with IGH on the der(14) and subsequent over expression of the BCL3 protein.

G-banded metaphase (left) showing the t(14;19)(q32;q13). The derivative chromosomes 14 and 19 are arrowed (bottom) G-banded karyogram showing the t(14;19)(q32;q13) and a add(15q) (top) - Courtesy Anthony V Moorman, Hazel M Robinson; R-banding (right).

Citation

Jean-Loup Huret

t(14;19)(q32;q13) IGH/CEBPA

Atlas Genet Cytogenet Oncol Haematol. 2008-05-01

Online version: http://atlasgeneticsoncology.org/haematological/1335/t(14;19)(q32;q13)-igh-cebpa

Historical Card

2004-09-01 t(14;19)(q32;q13) IGH/CEBPA by Hazel M Robinson,Anthony V Moorman Affiliation

Leukaemia Research Fund Cytogenetics Group, Cancer Sciences Division, University of Southampton, MP 822, Duthie Building, Southampton General Hospital, Southampton, SO16 6YD, UK