High expression of several tyrosine kinases and activation of the PI3K/AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma

Abstract

Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.

Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization

“…Considering that HRS cells are usually hyperploid, an estimation of the ploidy level was obtained as the mean value of copy numbers from 12 different loci (data not shown). 28,30 Copy numbers from FISH analyses of NOTCH1 and STAT6 were adjusted to the estimated ploidy levels of the cHL cases. The genomic status was then determined according to the following criteria: ratios of gene/ploidy level lower than 0.7 were considered as genomic loss, ratios between 0.7 and 1.3 as balanced, ratios higher than 1.3 and lower than 2 as genomic gains, and ratios above 2 as genomic amplifications.…”

“…The genomic status was then determined according to the following criteria: ratios of gene/ploidy level lower than 0.7 were considered as genomic loss, ratios between 0.7 and 1.3 as balanced, ratios higher than 1.3 and lower than 2 as genomic gains, and ratios above 2 as genomic amplifications. 28,30 For six of seven cHL cases studied for JUNB the ploidy levels were not available. In those cases, the JUNB genomic status was determined using the following criteria: signal copy numbers below 5 were defined as balanced (considering the characteristic tri-to tetraploidy of HRS cells), between 5 and 8 gained, and above 8 amplified.…”

The RON receptor tyrosine kinase is a potential therapeutic target in Burkitt lymphoma

“…19 Recent studies demonstrate that six RTKs, including RON, are expressed in Hodgkin/Reed-Sternberg HL cells and suggest that RON may be involved in the pathogenesis of HL. 20 Our results indicate that RON expression is significantly higher in BL and HL tissues than in normal lymph node and other lymphoma tissues. IHC staining showed that RON staining intensity and the number of positive cells are significantly higher in EBV + patients than in EBV -patients.…”

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

“…Thus, HRS cells express 8 RTKs, platelet-derived growth factor receptor (PDGFR) a, DDR2, EPHB1, RON, TRKA, TRKB, TIE1, and CSF1R, in varying patterns, and PDGFRa and TRKA have been shown to be activated in primary cases (5)(6)(7). As mutations affecting RTKs could not be detected in HRS cell lines and as activating ligands were frequently co-expressed in HRS cells or expressed by surrounding cells in the infiltrate of primary Hodgkin lymphoma cases (5), the receptors are presumed to be activated in an autocrine or paracrine fashion.…”