STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Abstract

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK + ALCL, 38% of ALK − ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK -ALCL (15%). Concurrent mutations were found in all subgroups except ALK + ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30 + phenotype representing primarily ALK − ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.Cancers 2020, 12, 702 2 of 17 diagnoses [1]. The most prevalent PTLCs are PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-negative (ALK − ALCL), and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK + ALCL) [2,3].Despite generally favorable response rates to chemotherapy, remissions are often not durable, and as such the natural history of PTCL is characterized by relapses and refractory disease. For this reason, upfront hematopoietic stem cell transplantation (HSCT) is often recommended in first remission for patients who are fit and have chemo-sensitive disease [4]. For patients who are not suitable for transplantation, chances of long-term disease control are very limited, with an average progression-free survival (PFS) of 5.5 months [5]. In this setting, optimal therapeutic approaches remain undefined representing an unmet clinical need.Recent advances in the molecular and genetic characterization of PTCL have helped to delineate differences and similarities between the various subtypes [6]. Several recurrent mutations have been identified in small subsets of patients potentially enabling more accurate disease classification and guide treatment decisions. In AITL, the three most commonly identified genetic lesions occur in the Tet methylcytosine dioxygenase 2 gene (TET2), the Ras homolog gene family, member A (RHOA), and the isocitrate dehydrogenase 2 gene (IDH2). Besides AITL, TET2 mutations can be seen with a high frequency also in PTCL-NOS with a T follicular helper cell phenotype [7]. RHOA, a small GTPase participating i...

STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

“…Moreover, no significant differences were found between mutation status of these genes with age, gender, disease stage, eastern cooperative oncology group performance status or age-adjusted international prognostic index (AA-IPI). As expected [ 9 , 13 , 15 ], expression of p-STAT3 (Y705) was detected at a high level in all ALK− ALCL patients harboring STAT3 mutations, although low/medium expression of p-STAT3 was also detected in STAT3 wild-type patient tumors (Fig. S4 , Table S6 ).…”

“…Despite the distinction between the two sALCL subtypes, frontline treatment for adults is similar and is based on CHOP or CHOEP, instead pediatric ALCL patients are mainly treated following the ALCL99 protocol [6][7][8]. Whilst high-throughput genomic studies in sALCL have shown recurrent genetic alterations, their association with outcome has not been fully investigated [9][10][11][12][13].…”

Targeting STAT3 and STAT5 in Cancer

“…JAK/STAT mutations were also identified in patients with the rare and aggressive T-cell prolymphocytic leukemia (T-PLL), pointing towards a possible mode of transformation [25]. Additionally, STAT3 (and not STAT5B) mutations were identified in multiple peripheral T-cell lymphomas (PTCL), as well as high pY-STAT3 expression, particularly in angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) patient samples, two different PTCL cancer types [26]. From an inhibition perspective, a derivatized indole was shown to be effective in both chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), as well as aggressive STAT5-N642H tumors [27].…”

Cytokines, Genetic Lesions and Signaling Pathways in Anaplastic Large Cell Lymphomas

“…Activating point mutations of STAT3 and/or JAK1 have been identified in 18% of nodal ALK- ALCLs and in 5% of C-ALCLs [ 50 ]. Another study of PTCL identified in ALK- ALCLs the highest rate of STAT3 mutations (38%) that may combine with JAK mutations (15%), while some ALK+ ALCLs (13%) presented STAT3 mutation alone [ 51 ]. The highest pY-STAT3 phosphorylation level is present in ALK- ALCL displaying a typical CD3-CD5- CD7- CD30+ phenotype [ 51 ].…”