Journal
ONCOGENE
Volume 32, Issue 26, Pages 3111-3118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.435
Keywords
cytokine signaling; LNK; hematopoiesis
Funding
- NIH [R01CA026038-32, U54CA143930]
- A * STAR Grant
- Mary Barry Foundation
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The signal transduction pathways, orchestrating the differentiation of hematopoietic stem and progenitor cells in response to cytokine stimulation, are strictly controlled by networks of feedback loops, highly selective protein interactions and finely tuned on/off switches. In hematological malignancies, the aberrant activation of signaling pathways is usually associated with mutations in tyrosine kinases. Recently, the role of negative signaling regulators is increasingly being recognized as an alternative mechanism involved in diseases such as leukemias and myeloproliferative neoplasms (MPNs). The adaptor protein LNK (Src homology 2 (SH2)B3) is a negative regulator of cytokine signaling that has an essential, nonredundant role in normal hematopoiesis. Indeed, LNK-deficient mice show marked expansion of early hematopoietic precursors, more mature myeloid and B-lineage lymphoid cells, as well as enhanced hematopoietic reconstitution. Murine models show that loss of LNK enhances the development of MPNs and may have a role in additional pathologies. LNK mutations were recently identified in patients with MPNs, and studies in animal models and hematopoietic cell lines suggest that LNK controls the aberrant signaling pathways induced by activated oncogenic kinases. In addition, genome-wide studies show that LNK is associated with autoimmune and cardiovascular disorders. These findings have implications for the future study of hematopoiesis, as well as for the development of novel stem cell and disease-specific therapies.
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