Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

Abstract

TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.

Cell of Origin and Immunologic Events in the Pathogenesis of Breast Implant–Associated Anaplastic Large-Cell Lymphoma

“…72,73 JAK1 and/or STAT3 mutations were found in 37.5% of ALK-negative sALCL specimens; fusion proteins involving the kinases TYK2 and ROS1, leading to constitutive STAT activation, were also identified, implicating STAT3 activation as a key oncogenic driver in this cancer type. 12,74,75 A study of whole exome sequencing on DNA extracted from effusion cytology fluid and germline DNA of two patients with effusion-limited BIA-ALCL revealed somatic, activating mutations in JAK1 and STAT3 as well as a germline JAK3 mutation, the latter suggesting a possible genetic risk factor for the development of this lymphoma. 12 Clinical specimens from 12 of 12 patients with BIA-ALCL tested positive for phospho-STAT3 (pSTAT3) by immunohistochemistry.…”

Direct Targeting Options for STAT3 and STAT5 in Cancer

“…Surprisingly, in a v-abl-driven model of STAT1 −/− leukemic cells initially harboring low MHC class I, enhanced MHC class I expression was gained during the disease progression, thereby reducing tumor recognition by NK cells [6]. As an exception, STAT1 was shown to be an oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL) and ALK + anaplastic large cell lymphoma (ALCL), and STAT1 is associated with the JAK2 exon 12 mutation in the progression of myeloproliferative neoplasms (MPNs) [7][8][9]. Reports on direct involvements of STAT2, STAT4 and STAT6 in cancerous processes are scarce and are not discussed here further [10].…”

Existence of reprogrammed lymphoma stem cells in a murine ALCL-like model

“…In summary, our results highlight the existence of a lymphoma stem cell population that originates from the DN3/DN4 cell population in a relevant NPM-ALK positive CD30-expressing ALCL-like mouse model, thereby providing the opportunity to test innovative treatment strategies (e.g., NPM-ALK-/JAK-/TYK2-inhibitors) [16], which aim to eradicate the lymphoma stem cell population and may overcome common treatment unresponsiveness due to low CD30 expression levels.…”

“…Molecular characterization of lymphoma stem cells and their activated pathways in ALCL may help in the design of targeted treatment strategies for the ALCL patient population [16][17][18][19]. It is a well-established principle, that therapies which eradicate the cancer stem cell population, assure higher long-term response with a lower recurrence rate than treatment regimens that focus on tumor mass reduction and may not affect cancer stem cells.…”