Molecular basis of aggressive disease in chronic lymphocytic leukemia patients with 11q deletion and trisomy 12 chromosomal abnormalities

Abstract

Abstract. In B-cell chronic lymphocytic leukemia (CLL), Rai stage, immunoglobulin gene mutational status, chromosomal abnormalities, CD38 and ZAP-70 expression were used as prognostic markers. In this study, to understand the molecular basis of chromosomal abnormalities leading to tumor progression, 90 CLL patients were grouped into poor prognosis (with 11q deletion and trisomy 12) and good prognosis (with normal karyotype and 13q deletion) and their clinical outcome was assessed. Gene expression profiles of 35 CLL samples with poor outcome (11q deletion, n=9; trisomy 12, n=5) and good outcome (13q deletion, n=13; normal karyotype, n=8) were analyzed using oligonucleotide microarray. Significance analysis of microarray (SAM) identified 27 differentially expressed genes between these two subgroups with significant overexpression of ATF5 and underexpression of CDC16, PCDH8, SLAM, MNDA and ATF2 in CLL patients with poor outcome. ATF5 gene expression in CLL was further studied because of its role in the regulation of cell cycle progression/differentiation and apoptosis. The overexpression of ATF5 was confirmed by real-time PCR using 39 CLL samples from the poor and good outcome groups. ATF5 was significantly (p<0.001) overexpressed in the poor outcome group. Furthermore, ATF5 expression was significantly higher in the 11q deletion as well as trisomy 12 group alone compared to the 13q deletion and normal karyotype groups. ATF5 overexpression was also associated with significantly (p=0.04) shorter time to treatment. Similarly, expression of five underexpressed genes also correlated with longer time to treatment. Thus, this report demonstrates that ATF5 may be one of the key genes involved in increased proliferation and survival in 11q deletion or trisomy 12, whereas CD16, CD86, SLAM, MNDA and ATF2 may be involved in the decreased proliferation of CLL cells with 13q deletion or normal karyotype.

Evaluation of flow cytometric assessment of myeloid nuclear differentiation antigen expression as a diagnostic marker for myelodysplastic syndromes in a series of 269 patients

“…The expression of MNDA in different human cells has been tested with different methods since its discovery. It has been detected in myelomonocytic precursors, monocytes, macrophages, subsets of normal B cells, AML blasts with maturation and certain B cell lymphomas, but not in other BM cells or nonhematopoietic cells, acute lymphatic leukemias, biphenotypic leukemias, AML without maturation and lymphatic blast crisis of chronic myeloid leukemia (23,26,(41)(42)(43)(44). Because both protein and gene expression of MNDA have been found at lower levels in patients with MDS (25,27,28) and given the availability of an MNDA-antibody applicable in MFC, the examination of MNDA expression by MFC is considered a potential discriminator between patients with MDS and those with other causes for cytopenias and healthy individuals.…”

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

“…Chromosome 11q deletion, 17p deletion and trisomy 12 were considered as the poor outcome group, whereas normal karyotype and 13q deletion were grouped as the better outcome group (22).…”

“…Most of the analyses were performed at p < 0.05 and FDR < 0.25, unless specified otherwise. The KaplanMeier method using the log-rank test was used to study the association of gene expression or clinical parameter with the clinical outcome as done previously (22,25). Time to treatment among CLL patients was used as an outcome and defined as the time period in months between diagnosis and initiation of the first treatment regimen.…”

Lenalidomide following fludarabine and rituximab in previously untreated CLL

“…We also found Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) transmembrane receptor levels to be 5-fold decreased; whose reduced expression has been reported to correlate with shorter time to treatment and poor prognosis [17,18]. Although limited by availability and sample size, the results from our correlative analyses provide a framework for further hypothesis generation and will be validated in larger datasets.…”