Degradation of BCL-XL by Activated p38 Pathway Plays a Key Role in Myelodysplastic Syndromes (MDSs) — Revealed by Reverse Phase Protein Array (RPPA) and Computational Mathematical Model.
Lixin Zhang, Jianguo Wen, Youli Zu, April Ewton, Huiming Peng, Xiaobo Zhou, Chung-Che Chang. Methodist Hospital & Weill Cornell Medical College, Houston, TX; Methodist Hospital Research Institute, Houston, TX
Background: MDSs are a heterogeneous group of clonal hematopoietic stem cell diseases characterized by dysplasia and ineffective hematopoiesis. Immune mechanisms driven by autoreactive T cell clones and associated cytokines such TNF-alpha have been associated with the ineffective hematopoiesis in MDS.
Design: We examined dynamic changes of key signaling proteins (including JNK and p38 MAPK pathways) in bone marrow mononuclear cells from controls and MDS patients activated in vitro by TNF-alpha at various time intervals using RPPA. The resulting findings were analyzed by a novel computational model developed in our laboratory and preliminarily validated by immunohistochemistry using paraffin embedded core biopsies from MDS patients (n= 12).
Results: Our model suggested that the dynamic response patterns for JNK and P38 MAPK after TNF-alpha stimulation in MDS cells were different from normal marrow cells. BCL-XL degradation was induced by JNK pathway in normal controls, but by p38 MAPK pathway in MDS patients (fig1).
By immunohistochemistry, BCL-XL was highly expressed on hematopoietic cells from normal marrows, but was minimally expressed on MDS marrows (fig2).
Additionally, staining for phosphorylated p38 MAPK-alpha showed much higher p38 MAPK activation in MDS marrows, suggesting overactivation of p38 MAPK enhanced degradation of BCL-XL in MDS.
Conclusions: The combination of RPPA and computational mathematical modeling is a powerful tool for comprehensive investigation of the cellular changes for diseases with complex pathogenesis. The degradation of BCL-XL (a key anti-apoptotic protein) by p38 MAPK over-activation as revealed may contribute to the increasing apoptosis, a phenomenon commonly observed in MDS marrow cells and lead to ineffective hematopoiesis.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 163, Monday Morning