Background: Primary mediastinal large B cell lymphoma (PMLBCL) is a rare subtype of non-Hodgkin lymphoma mostly diagnosed in young women and is currently recognized as a distinct clinical and biological entity. First line therapy with R-CHOP allows to achieve good remission rates even if chemoresistant cases remain highly challenging from the therapeutic standpoint. As such, we aimed to compare the transcriptome of R-CHOP resistant PMBCL patients to those of chemosensitive patients.
Methods:We extracted RNA from embedded paraffin samples and then we performed whole RNA sequencing on 7 patients. Four of them were selected as chemoresistant (Group A), while three of them were classified as responder to R-CHOP (Group B). A First bioinformatics analysis selected a panel of 200 genes significantly differentially expressed in chemoresistant (A) samples versus chemosensitive (B). An unbiased analysis based on different ontology of the genes led to easily identify common signatures that may better profile the two groups of patients. Finally, on a bias analysis, genes were divided into categories in order to identify potential new targets and/or mechanisms of chemoresistance.
Results:We identified three genes which may be frankly related to chemoresistance in PMLBCLs due to an overexpression in the group A or a suppression of expression in group B. We selected NFKBIA, the gene which encodes for the IκBα protein, mutated in numerous Hodgkin's lymphoma cells, which cause NFkB to be chronically active in the lymphoma tumor cells. For this reason, we imagine that it could have a major role in the modulation of PMLBCLs sensitivity to chemotherapy.
EPHB1 was selected for its very strong expression in the poor prognosis group, since it is one of the most expressed genes and for his association with numerous cancers. The kinase STK 33 appeared overexpressed in group A. A more thorough investigation of this gene might lead to new, significant findings.
Our in-silico analyses allowed to identify in PMBCL an unique profile that may modulate sensitivity to chemotherapy. Further analyses may address whether this unique phenotype has clinical implications. We may expect to: i) develop specific therapeutic strategies to target NFkB, EPHB1 and STK33 pathways in PMBCL with a chemoresistant behaviour; ii) correlate the expression profile of resistant PMBCL to other transcriptomes, including those of Hodgkin Lymphomas, Diffuse Large B cell Lymphomas, in order to better profile clinical and biological overlapping features.
Saglio:Ariad:Research Funding;Incyte:Research Funding;Roche:Research Funding;Bristol-Myers Squibb:Research Funding;Pfizer:Research Funding;Novartis:Research Funding.
Asterisk with author names denotes non-ASH members.