Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases. In addition to intrinsic genetic alterations, the effects of the extrinsic microenvironment also play a pathological role in MDS development. The presence of increased inflammatory
cytokines, such as
tumor necrosis factor-alpha (TNF-α), in marrow and abnormal activation of the
p38 mitogen-activated protein kinase (MAPK) signaling pathway in hematopoietic cells are associated with the ineffective hematopoiesis in MDS. However, the molecular mechanism of
p38 MAPK activation triggered by microenvironment
cytokines remains poorly understood. To address this question, we combined computational modeling analysis and molecular biology studies to perform a systematic investigation of signaling events regulated by microenvironment
cytokines in hematopoietic cells from MDS patients. We examined dynamic changes of key signaling events, including the
p38 MAPK and the
c-Jun N-terminal kinase (JNK) pathway in bone marrow mononuclear cells from MDS patients or normal donors in response to TNF-α stimulation using reverse phase
protein array technology. The results were analyzed by a novel computational model and preliminarily validated by immunohistochemistry analysis of the bone marrow tissues from twelve MDS patients and normal donors. Our systematic model revealed that the dynamic response patterns of
p38 MAPK and JNK to TNF-α stimulation in MDS were different from that observed in normal marrow cells. Particularly,
B-cell lymphoma-X (
BCL-XL) protein degradation was regulated by the JNK pathway in normal cells, but by
p38 MAPK in MDS cells. By immunohistochemistry, BCL-XL was highly expressed in hematopoietic cells from normal marrow, but was minimally expressed in MDS marrow. Additionally, immunostaining for phosphorylated p38 MAPKα showed much higher
p38 MAPK activation in MDS marrows, supporting over-activation of
p38 MAPK-enhanced degradation of BCL-XL in MDS. The degradation of BCL-XL triggered by
p38 MAPK over-activation may contribute to the increasing apoptosis of marrow cells, a phenomenon commonly observed in MDS, and lead to ineffective hematopoiesis. Our study suggests that the combination of molecular
biological studies and systematic modeling is a powerful tool for comprehensive investigation of the complex cellular mechanisms involved in MDS pathogenesis.