High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma

Abstract

Aim: To gain more insight into the genes involved in the aetiology and pathogenesis of anaplastic large cell lymphoma (ALCL). Methods: Serial analysis of gene expression (SAGE) was undertaken on the CD4+ALK+ (anaplastic lymphoma kinase positive) ALCL derived cell line Karpas299 and as comparison on CD4+ T cells. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were performed on five ALCL derived cell lines and 32 tissue samples to confirm the SAGE data. Results: High expression of Mcl-1 was seen in the Karpas299 cell line, whereas the two other antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-X L , were not detected in the SAGE library. Quantitative RT-PCR confirmed the high expression of Mcl-1 mRNA and low expression of Bcl-2 and Bcl-X L in Karpas299 and in four other ALCL cell lines. To expand on these initial observations, primary tissue samples were analysed for Mcl-1, Bcl-X L , and Bcl-2 by immunohistochemistry. All 23 ALK+ and nine ALK2 ALCL cases were positive for Mcl-1. Bcl-2 and Bcl-X L were expressed infrequently in ALK+ ALCL cases, but were present in a higher proportion of ALK2 ALCL cases. Conclusion:The consistent high expression of Mcl-1 in ALK+ and ALK2 ALCL suggests that Mcl-1 is the main antiapoptotic protein in this disease. The high frequency of Mcl-1, Bcl-2, and Bcl-X L positive ALCL cases in the ALK2 group compared with the ALK+ group indicates that ALK induced STAT3 activation is not the main regulatory pathway in ALCL.

MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression

“…8 MCL-1 expression could compensate for the lack of immunohistochemically detectable BCL-2 and BCL-XL expression in ALK ϩ ALCL. [9][10][11] Some studies have suggested that the Jak-STAT and PI3K pathways activated in ALK ϩ tumors could be involved in up-regulating MCL-1 but other pathways at the posttranscriptional level, such as microRNAs, might also contribute to its high expression in ALK ϩ ALCL cases (see reviews by Akgul 12 and Michels et al 13 ).…”

“…8 MCL-1 expression could compensate for the lack of immunohistochemically detectable BCL-2 and BCL-XL expression in ALK ϩ ALCL. [9][10][11] Some studies have suggested that the Jak-STAT and PI3K pathways activated in ALK ϩ tumors could be involved in up-regulating MCL-1 but other pathways at the posttranscriptional level, such as microRNAs, might also contribute to its high expression in ALK ϩ ALCL cases (see reviews by Akgul 12 and Michels et al 13 ).Micro-RNAs (miRNAs) are small noncoding RNAs that regulate target gene expression posttranscriptionally through base pairing within the 3Ј-UTR regions of the target messenger RNAs and inducing their degradation, translational inhibition, or both of the encoded proteins. 14,15 MiRNAs play key regulator roles in fundamental biologic processes including cell differentiation, apoptosis, cell proliferation, organ development, and hematopoiesis (see review by Kluiver et al 16 ).…”

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

“…Nevertheless, it is conceivable that ALK-mediated transformation requires a more complex scenario. Comprehensive analyses of the transcriptome of ALK-positive ALCLs are limited and derived from a small number of fresh tissues or ALK-positive cell lines (20)(21)(22)(23). Since ALCL cells often represent a minority within pathological samples and the normal counterpart of ALCL cells is not known, these studies could not be considered paradigmatic.…”

Pharmacology and clinical potential of oblimersen sodium in the treatment of chronic lymphocytic leukemia

“…25,26 Mcl-1 is also overexpressed in anaplastic large cell lymphoma, suggesting that this may be the predominant antiapoptotic pathway in this lymphoma. 27 In contrast, Bcl-2 and Bcl-XL are more frequently expressed in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. 27 A defect in the apoptotic pathway is a hallmark of chronic lymphocytic leukemia (CLL), and differences in chemosensitivity may be attributable to Bcl-2 expression in CLL cells.…”

“…27 In contrast, Bcl-2 and Bcl-XL are more frequently expressed in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. 27 A defect in the apoptotic pathway is a hallmark of chronic lymphocytic leukemia (CLL), and differences in chemosensitivity may be attributable to Bcl-2 expression in CLL cells. [28][29][30] Whereas Bcl-2 gene rearrangements are absent in CLL, Bcl-2 protein is overexpressed in CLL cells, 31 indicating that disturbances in the balance between proapoptotic and antiapoptotic proteins may determine the susceptibility of cells to apoptotic signals.…”