The role of the JAK-STAT pathway in B cell lymphoma
B cell lymphoma is the most common form of blood cancer, and causes the ninth cancer related mortality in the United States. Recent genome sequencing studies have identified a large set of candidate genetic alterations implicated in the cancer. However, it remains challenging to determine the causal role of each genetic change in disease risk and pathology, largely because of remarkable heterogeneity of the disease.
To address this challenge, we intend to define genetic alterations, to elucidate their tumorigenic mechanisms in main types of B cell lymphoma, and to identify new molecular targets in their oncogenic pathways for therapeutic development. In particular, we will focus on molecular mechanisms of the JAK-STAT pathway in lymphomagenesis. Using cutting-edge technologies, we have characterized a typical genetic alteration in primary mediastinal and Hodgkin lymphoma, i.e., amplification of the p24 segment of chromosome 9. The amplicon includes tyrosine kinase JAK2, a gene for which expression is essential for cell survival.
In addition to signaling through STAT6 phosphorylation, JAK2 regulates gene transcription and promotes cancer cell survival through a recently discovered mechanism in which histone H3 is phosphorylated on tyrosine 41. Very recently, we found that the same histone modification can be catalyzed by the homologous JAK1 kinase in the most common B cell lymphoma, termed diffuse large B-cell lymphoma. How JAK1 regulates gene expression to promote cancer cell survival through this epigenetic mechanism will be our current research interest.