Hodgkin Lymphoma requires stabilized NIK and constitutive RelB expression for survival

STELLA MARIS RANUNCOLO; WENMING XIAO; GEORGE WRIGHT; MONES ABU-ASAB; STEFANIA PITTALUGA; ELAINE S. JAFFE; BRIAN A. LEWIS

Philadelphia, Penssylvania

Congreso; 103rd Annual Meeting of the American Association for Cancer Research (AACR); 2012

American Association for Cancer Research (AACR)

The REL family of transcription factors plays major roles in diverse cell processes and tumor etiology. Despite considerable evidence supporting the role of the REL members in the immune system and lymphomagenesis, it is not clear whether each REL controls unique targets in distinct subsets of B cell-derived lymphomas or whether each is redundant. We delivered specific shRNAs to knock down each REL member in representative non-Hodgkin (NHL) and Hodgkin lymphoma (HL) cell lines. All NHL and HL cell lines were dependent on RelA and c-Rel for survival but only HL cells were sensitive to RelB depletion. ChIP-seq analysis uncovered an extensive nonoverlapping REL networks and that RelB directly controlled cell cycle regulators and apoptosis inhibitors including BCL2 and BCLx. However, the RelB shRNA in HL cells does not kill these cells by apoptosis. Electron microscopy revealed intact nuclei with considerable numbers of cytosolic vacuoles, indicative of autophagy. Secondly, ATG7, a key player in the autophagosomes development, is induced. We found that HL cell lines and primary tumors stably expressed NIK and that HL cell lines are missing either TRAF2 or TRAF3 protein (negative regulators of NIK). Unexpectedly, RelB shRNA resulted in the re-expression of TRAF2 and degradation of NIK protein. Lastly, both NIK shRNA and a small molecule inhibitor of NIK had the same phenotype as the relB shRNA. These data shed light on unexplored aspects of HL biology. We found that HL is the only GC B-cell derived malignancy that relies on RelB for viability, and thus differentiates Hodgkin lymphoma from non-Hodgkin lymphomas. These data argue that each REL member has specific and unique functions and gene targets, as we predicted from the lack of similarities in their transactivation domains. Furthermore, the RelB dependency in HL suggests that NIK is an attractive therapeutic target and the possibility of targeting NIK enzymatic activity in HL patients with diminishing side effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-281. doi:1538-7445.AM2012-LB-281 ©2012 American Association for Cancer Research