Trisomy 12 in B Cells of Patients with B-Cell Chronic Lymphocytic Leukemia

Abstract

Trisomy 12 is the most frequently reported chromosome abnormality in patients with B-cell chronic lymphocytic leukemia, but only normal karyotypes are found in one third of patients with that disorder. Moreover, samples from patients with trisomy 12 also have many normal metaphases. To identify immunologically the cells in which both the trisomy 12 and the normal karyotypes occur, we studied two patients with B-cell chronic lymphocytic leukemia--one whose neoplastic cells demonstrated lambda light-chain clonality and one whose cells had kappa light-chain clonality. We used a recently developed cytogenetic method that allows simultaneous analysis of cell morphology, immunologic phenotype, and karyotype in the same mitotic cell. In cultures of blood cells stimulated with pokeweed mitogen and tetradecanoylphorbol acetate, all the mitotic cells with either the lambda or the kappa immunoglobulin had trisomy 12, whereas all the cells that lacked these light chains or that had T-cell markers (OKT8 or OKT4) had normal karyotypes. These results show that trisomy 12 in B-cell chronic lymphocytic leukemia occurs in the neoplastic B cells, but not in the T cells, and they thus provide an explanation for the common finding of mitoses with normal karyotypes in patients with B-cell chronic lymphocytic leukemia.

Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia

“…by guest www.bloodjournal.org From aberrations can be identified twice as frequently as they are by chromosome banding after stimulation with classic B-cell mitogens and at even higher frequency (82%) compared with the routinely used interphase FISH. 3,[6][7][8][9][10][11][12][13]24 Most important, we observed translocations in approximately one third of studied patients, though those aberrations were considered rare events in CLL. 25,26 Half the translocations appeared to be balanced in the banding analysis; however, the presence of small deletions or duplications at the breakpoints cannot be ruled out with certainty.…”

“…However, these timeconsuming metaphase analyses were completely replaced by interphase FISH and fell into oblivion. [6][7][8][9][10][11][12][13] After stimulation with CD40L or CpG-ODN, we are now able to detect chromosomal aberrations in approximately 90% of patients with CLL. In fact, der(2)t(2;16)(p11;p13) [16] der(4)t(2;4)(p21;q13) [16] der (7)t(4;7)(q13;q22) [16] der(13)t(7;13)(q22;q14) [16] der (16) der(1)t(1;6)(q25;p11) [4] der(3)t(3;5)(q21;q13) [4] der (6) der(11)t(4;11)(q11;p13) [2] ins(11;13)(q12;q21q34) [2] der(8)(ins8;15)(p12;qq) [2] der (18) t(4;7)(q23;q11.2) [2] der(4)t(4;7)(q23;q11.2) [2] der(6)t(6;7)(p21;q11.1) [2] der (7) [11] del(13)(q12q14) [11] t(1;15;19)(p36;q15;p11) [11] t(12;14)(q13;q32) [11] der(3)(3;11)(p25;q22) [ [7] del(11)(q13q22) [11] del(13)(q12q22) [7] t(3;6)(p21;p22) [4] t ( t(1;1)(p36;q10) [18] t(10;18)(q21;q21) [18] der (17) t(12;18)(q23;q21) [3] der (17) (1)t(1;6)(q21;?)…”

“…[1][2][3][4][5] Cytogenetic analyses in CLL were performed in the 1980s evaluating metaphases that were obtained after stimulation with B-cell mitogens such as TPA. [6][7][8][9][10][11][12][13] Although chromosomal aberrations were detected by this approach in 40% to 50% of patients, this technique and its prognostic implications were mostly replaced when interphase fluorescence in situ hybridization (FISH) became available. Nowadays, chromosome analysis is usually performed by interphase FISH using a probe set that, according to our current knowledge, covers regions often involved in numerical or structural rearrangements.…”

Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

“…We detected significantly higher SMOH expression in groups with unfavorable cytogenetic abnormalities compared with normal karyotypes (P ¼ 0.035), as increased SMOH expression was observed in patients with trisomy 12 (Tri12; Figure 2a). Tri12 is present in about 20-40% of CLL cases with cytogenetic abnormalities and correlates with atypical histology (Knuutila et al, 1986;Dohner et al, 1999). Although SMOH (P ¼ 0.051) and other critical components upstream of GLI, such as Suppressor of Fused (P ¼ 0.046) and PTCH2 (P ¼ 0.218), were significantly, or by trend, increased in the prognostically unfavorable group of patients with unmutated immunoglobulin heavy chain variable (Figure 2b), GLI1 levels were not influenced by any tested risk parameter.…”

Aurora-A kinase nuclear expression in chronic lymphocytic leukemia

“…[24][25][26] Up to 15% of patients with CLL show progressive disease associated with chromosomal abnormalities, including trisomy 12, p53 gene mutations, and ATM gene deletion. Of these three abnormalities, trisomy 12 is most common (15-20% of cases), [27][28][29] which may occur alone or with deletions or translocations of chromosome 13q14 (25% of cases).…”