No abstract

A series of 105 patients with acute promyelocytic leukemia (APL) has been cytogenetically investigated at the Department of Hematology of the Saint-Louis Hospital (Paris) between 1977 and 1990. Sixty-two patients were examined at diagnosis, 32 in relapse, and 11 both at diagnosis and in relapse. The typical t(15;17)(q22;q12) or variants of this translocation were observed in all but four patients. The t(15;17) was the only change in 47 cases at diagnosis and in 21 examined in relapse. The most frequent secondary change was trisomy 8 (17% at diagnosis). More or less complex chromosomal abnormalities in addition to t(15;17) were present in six patients at diagnosis, and in 17 patients in relapse. Rearrangements of 2q35-q37 and del(11p) were observed only in relapse and may thus be nonrandom secondary changes. Cytogenetic studies performed on 19 patients treated with all-trans retinoic acid did not indicate that this treatment induces chromosomal abnormalities.

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 ¼ 3) compared to other T-ALLs (total, n ¼ 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.