Id4 is deregulated by a t(6;14)(p22;q32) chromosomal translocation in a B-cell lineage acute lymphoblastic leukemia.
OBJECTIVE
Chromosome translocations resulting in gene overexpression are commonly associated with lymphoid neoplasia. Enhancer elements of the immunoglobulin or T-cell receptor (TCR) loci are abnormally located in the vicinity of the entire coding sequences of genes which exert an influence on the normal maturation and differentiation program of lymphoid cells.


METHODS
A patient who presented with a B-cell lineage acute lymphoblastic leukemia had a t(6;14)(p22;q32). Cytogenetic and molecular findings confirmed the involvement of IgH. Molecular cloning of the breakpoint revealed that this was located near the coding sequence of the Id4 gene, a helix-loop-helix (HLH) inhibitor protein. Alu-repeated sequences at the 6p22 end flanked a short stretch of 10 bases shared by the 6p22 and 14q32 ends, suggesting that a deletion or a looping-Alu mediated mispairing mechanism may lead to this chromosome translocation.


RESULTS
Northern blot and real-time polymerase chain reaction analyses showed that the Id4 mRNA was abnormally overexpressed in this case. Only the two smaller Id4 mRNA products were detected (1.6 and 1.1 kb). Immunohistochemical analysis of Id4 protein was also assayed in a series of hematologic malignancies. Marked overexpression was found in two cases of T-cell prolymphocytic leukemias and in four B-cell lineage acute lymphoblastic leukemia including one case with the t(8;14) and another case with a p53 mutation.


CONCLUSIONS
The Id4 gene may behave as an oncogene in some human leukemias, perhaps through its capacity to sequester specific B-cell transcription factors. A genetic recombination between Alu-repeated sequences may not be the exclusive mechanism of generating pathogenic chromosomal translocations.
Bellido
Mar
M
Laboratori d'Hematologia, Hospital de la Santa Creu i Sant Pau, Avda Sant Antoni M. Claret 167, 08025 Barcelona, Spain.
Aventín
Anna
A
Lasa
Adriana
A
Estivill
Camino
C
Carnicer
Maria J
MJ
Pons
Cristina
C
Matías-Guiu
Xavier
X
Bordes
Ramón
R
Baiget
Montserrat
M
Sierra
Jorge
J
Nomdedéu
Josep F
JF
D000328:Adult; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000502:physiology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D014157:Transcription Factors