Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias.
Strong expression of at least one of the three D-type cyclins is common in human cancers. While the cyclin D1 and D3 genes (CCND1 and CCND3) are recurrently involved in genomic rearrangements, especially in B-cell lymphoid neoplasias, no clear involvement of the cyclin D2 gene (CCND2) has been reported to date. Here, we identified chromosomal translocations targeting the CCND2 locus at 12p13, and the T-cell receptor beta (TCRB) or the TCRA/D loci in T-cell acute lymphoblastic leukemias (T-ALLs). Expression analysis demonstrated dramatic cyclin D2 overexpression in the translocated cases (n=3) compared to other T-ALLs (total, n=89). In order to evaluate dysregulation in T-ALL with respect to normal T-cell differentiation, we analyzed CCND2 expression in normal purified human thymic subpopulations. CCND2 levels were downregulated through progression from the early stages of human T-cell differentiation, further suggesting that the massive and sustained expression in the CCND2-rearranged T-ALL cases was oncogenic. Association with other oncogene expression (TAL1, HOXAs, or TLX3/HOX11L2), NOTCH1 activating mutations, and/or CDKN2A/p16/ARF deletion, showed that cyclin D2 dysregulation could contribute to multi-event oncogenesis in various T-ALL groups. This report is the first clear evidence of a direct involvement of cyclin D2 in human cancer due to recurrent somatic genetic alterations.
Clappier
E
E
Genome Rearrangements and Cancer Group, INSERM U728 and Institut Universitaire d'Hematologie, Hôpital Saint-Louis and Paris 7 University, Paris, France.
Cuccuini
W
W
Cayuela
J M
JM
Vecchione
D
D
Baruchel
A
A
Dombret
H
H
Sigaux
F
F
Soulier
J
J
D000328:Adult; D002469:Cell Separation; D002648:Child; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics*; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D015321:Gene Rearrangement; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D014178:Translocation, Genetic
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D011948:Receptors, Antigen, T-Cell