Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity

Abstract

Chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) have been shown to correlate with prognosis. Little is known about the relationship between chromosomal abnormalities and biological behavior of B-CLL cells in vitro. The present study was designed to explore the impact of chromosomal abnormalities determined by interphase fluorescence in situ hybridization (FISH) on the in vitro survival and immunogenicity of B-CLL. Considerable heterogeneity was noted in the in vitro survival and expression of costimulatory, adhesion, and antigen-presenting molecules by B-CLL cells. Spontaneous apoptosis of B-CLL cells in vitro was significantly lower in samples with good prognosis cytogenetics when compared to samples with poor prognosis cytogenetics. In contrast, B-CLL cells from samples with good prognosis cytogenetics exhibited higher basal expression of molecules involved in costimulation, cellular adhesion, and antigen presentation, and induced significantly more T-cell proliferation in mixed lymphocyte cultures. We conclude that chromosomal aberrations of B-CLL cells correlate with the in vitro biological behavior of B-CLL. Our data indicate that good prognosis cytogenetics correlates with less spontaneous apoptosis but greater in vitro immunogenicity. These findings could have significant implications on the design of future therapeutic approaches in patients with CLL, and the likelihood of response based on cytogenetics.

Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia

“…However, there is no study on the prognostic significance of del(13q) on the response to therapy. Others have found higher bcl-2 expression in B-CLL cells with del(13q) or normal karyotype as compared to the bad prognosis groups del(17p), trisomy 12 or del(11q), which is in agreement with our results (Jahrsdörfer et al, 2005). In addition, the expression of two microRNAs, miR-15a and miR-16-1, is inversely correlated to bcl-2 expression in B-CLL samples and they negatively regulate bcl-2 at a post-transcriptional level (Cimmino et al, 2005).…”

The effects of CpG ODN on CLL proliferation, apoptosis or phenotype could have an impact on its clinical utility

“…This in vitro finding was consistent with the in vivo demonstration of higher LDH levels in patients with poor prognosis CLL. 3 Together, our results and those of Longo suggest that poor prognosis CLL is accompanied by a higher CLL cell turnover (that is, both proliferation and apoptosis). Given this finding, it is important to recognize that equating a tendency of poor prognosis CLL to proliferate in response to CpG ODN with a lack of potential clinical efficacy does not take sensitivity to apoptotic signals into account.…”

“…(b) CD3 þ T cells from a buffy coat of a healthy blood donor were isolated by negative selection using magnetic beads and CFSE-labeled. 3 These T cells were cocultured for 5 days with CLL cells (CD19 þ cells) from seven subjects with different cytogenetics in the presence or absence of CpG ODN (2.5 mg/ml). The CLL-cell/T-cell ratio was 1:5.…”

Reply to ‘Jahrsdorfer et al.’

“…Poor prognosis CLL cells had significantly lower levels of immunologically relevant surface proteins (costimulatory, antigen-presenting and cell adhesion molecules) compared to CLL cells from the good prognosis group. 3 Functionally, CLL cells from the poor prognosis group induced less T-cell proliferation in mixed lymphocyte cultures than CLL cells from the good prognosis group. We previously published that CLL cells respond to CpG ODN by increasing the expression of these molecules.…”

“…Patients with short bcr2 transcripts as a consequence of exon 6 PML deletions are referred as V-form PML-RARa. [2][3][4] In this work, we report an unusually large exon 6 PML deletion (161 bp) associated with a short intron capture (5 bp), giving rise to a net 156 bp deletion (52 amino acids). The outcome was good.…”