Hedgehog Signaling Pathway Is Aberrantly Activated in a Subset of High Grade Lymphomas
WO Greaves, JE Kim, K Kunkalla, LJ Medeiros, R Singh, F Vega. The University of Texas MD Anderson Cancer Center, Houston, TX; Seoul National University, Boramae Hospital, Seoul, Korea
Background: The Hedgehog (Hh) proteins (Sonic, Indian and Desert) are secreted signaling molecules that play an integral role in normal embryonic development. Critical components of this pathway are the receptors, patched (PTCH) and smoothened (SMO), and the transcriptional regulators, GLI1, 2 and 3. Nuclear GLI1 is an indicator of the pathway activation status. SMO inhibitors are currently availble. We assessed Hh pathway proteins in large number of cases of non-Hodgkin lymphoma (NHL) and HL.
Design: The study group included 194 NHL and 55 HL. NHL cases included 64 DLBCL, 27 FL, 14 TCHRBCL, 6 PMBCL, 13 BL, 9 MCL, 9 SLL/CLL, 8 MZL, 22 ALK+ ALCL, 11 ALK- ALCL, and 11 PTCL. HL cases were 41 cHL and 14 NLPHL. Hh, and GLI1 proteins were immunohistochemically assessed in tissue microarray and/or routine sections. Protein expression was scored as negative, low (+1), or high (+2) depending on the staining signal intensity as compared to intrinsic staining of histiocytes and dendritic cells. Sonic, Indian, Desert, SMO, PATCH and GLIs were asssesed by western blot (WB) and RT-PCR in 12 DLBCL cell lines.
Results: Based on GLI1 expression, DLBCL, TCHRBCL, ALCL and PTCL showed activation of the Hh pathway (table). Low or no expression of GLI1 were detected in BL, MCL, SLL/CLL, MZL, FL, NLPHL and cHL. WB and quantitiative RT-PCR assays revealed that Indian and Dessert were the Hh molecules more highly expressed in DLBCL cell lines. SMO was highly expressed in 9 of 12 (75%) DLBCL cell lines.
Conclusions: Hh signaling is activated in a subset of high grade NHL, in particular DLBCL. DLBCL cells produce high levels of Indian and Desert. Most DLBCL cell lines express high levels of SMO, suggesting a possible therapeutic role for SMO inhibitors in DLBCL.
|Lymphoma Histologic Type||*GLI1|
|T-cell/histiocyte-rich large B-cell lymphoma (TCHRBCL)||87.5%|
|Diffuse large B-cell lymphoma (DLBCL NOS)||42%|
|ALK+ anaplastic large cell lymphoma (ALCL)||36%|
|Peripheral T-cell lymphoma (PTCL)||14.3%|
|Primary mediastinal B-cell lymphoma (PMBCL)||0%|
|Burkitt lymphoma (BL)||0%|
|Mantle cell lymphoma (MCL)||0%|
|Small lymphocytic lymhoma/CLL||0%|
|Marginal zone lymphoma (MZL)||0%|
|Follicular lymphoma (FL)||0%|
|Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)||0%|
|Classical Hodgkin lymphoma||0%|