Refractory and relapsed predicitive biomarkers in Hodgkin Lymphoma and potential directed-therapy targets.

GAMBOA-CEDEÑO, ANGÉLICA; CASTILLO, MARIÁNGELES; OTERO, VICTORIA; SCHUTZ, NATALIA; FANTL, DOROTEA; CUGLIARI, SILVANA; MARTA E. ZERGA; JAUK VITALI, FEDERICO; GARCÍA RIVELLO, HERNÁN; ERICA A. ROJAS BILBAO; NUÑEZ, MYRIAM; RANUNCOLO, STELLA MARIS

CABA

Jornada; VI Jornada de Investigación y 15° Premio Prof. Dr. José Tessler del Hospital Italiano de Buenos Aires.; 2018

Hospital Italiano de Buenos Aires (HIBA)

Hodgkin lymphoma (HL) is a lymphatic system malignancy derived from germinal center B cells. Despite chemosensitive stage I HL patients can achieved 90% of response this drops to 60% in late stages. There is no alternative treatment for refractory and relapsed patients. Furthermore, rescue chemotherapy schemes brigs along high risk of acute and late toxicity. This and the young age of diagnosis highlight the need to better understand HL molecular biology. There currently no molecular biomarkers to predict refractory nor risk of relapse at diagnosis. We have previously reported that HL relies on the alternative NFkB pathway, mediated by reB/NIK, to survive. Its constitutive activativation is the result of stable NIK protein expression both in human HL cell lines and patient biopsies. Depletion of either relB or NIK by shRNAs or pharmacological NIK inhibitors induce HL cell death. Furthermore we uncovered Rel-B target genes by ChIP-Seq which showed relB bound to Bcl2 promoter, among other cell cycle control genes. We detected a significant downregulation of both Bcl2 mRNA and protein levels, following relB or NIK knockdown, indicating relB direct regulation. Our molecular studies suggested that NFkB alternative pathway constitutive activation could explain the non-responding cases of HL. We aimed to analyze whether mediators of this pathway could be used as predictive biomarkers and play a role as potentially targetable factors in both refractory and at risk of relapse HL patients.We analyzed the citoplasmic NIK and BCL2 expression in HRS cells of lymphatic node biopsies of 96 HL patients by inmunohistochemistry [50 female Md age and (range) 59 (6-82) and 46 male 42 (9-78)]. The univariate analysis showed no correlation among NIK nor BCL2 expression and the prognosis clinical and pathological parameters in HL patients. As prevously suggested by ChIP experiments a positive correlation was found between NIK and BCL2 expression (p=0.02). We found that more tan 30% of HRS positive for NIK and/or BCL2 correlated with lack of response to conventional therapy or progression (p=0.004).NIK and BL2 could be used as predictive markers of refratory and at risk of early relapse in HL patients at diagnosis. Furthermore they represent interesting potential therapeutic targets. Bcl2 inhibitos have already been aproved to be use in other onco-hematological pathologies.