We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-kB signaling pathways and frequent B2M alterations that limit MHC class I expression, as in cHL.
In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.
Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including <i>STAT3</i>, <i>STAT5B</i>, <i>JAK1</i>, <i>JAK2</i>, and <i>PTPN1</i>), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.
Moreover, several signal transduction pathways that are critical for the proliferation and survival of neoplastic Hodgkin Reed-Sternberg (HRS) cells, including NF-κB, JAK-STAT, PI3K-AkT and ERK, are deregulated in cHL.
Given the proven oncogenic potential of this novel fusion, our studies provide new insights into the pathogenesis of cHL and indicate that in at least some cases, constitutive activation of the JAK/STAT pathway is caused by JAK2 rearrangements.
We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively.