STAT3 mutations are frequent in CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia

Abstract

11These authors contributed equally to this work. REFERENCES 1 Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91-97. 2 Koreth J, Cutler CS, Djulbegovic B, Behl R, Schlossman RL, Munshi NC et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 2007; 13: 183-196. 3 Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 2011; 117: 6063-6073. 4 Moreau P, Avet-Loiseau H, Harousseau JL, Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies. J Clin Oncol 2011; 29: 1898-1906. 5 Harousseau JL, Avet-Loiseau H, Attal M, Charbonnel C, Garban F, Hulin C et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 Trials. J Clin Oncol 2009; 27: 5720-5726. 6 Chanan-Khan AA, Giralt S. Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol 2010; 28: 2612-2624. 7 Moreau P, Attal M, Pé gourié B, Planche L, Hulin C, Facon T et al. Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial. Blood 2011; 117: 3041-3044.

Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

“…Although STAT3 or STAT5B mutations have been reported in malignancies such as B-cell lymphomas 23 , angioimmunoblastic T-cell lymphoma 24 , CD30 þ T-cell lymphoma 25 , the indolent LGLL diseases [26][27][28] and recently in T-cell prolymphocytic leukaemia 29 , which also included functional characterization of STAT5 mutations, our study describes prevalent activating STAT5B and STAT3 mutations in aggressive lymphomas of NK and gd-T cell of origin. Importantly, we provided strong in vitro functional data that support an oncogenic role of these mutants as well as mechanistic insight into how the N642H mutant acquires enhanced functional activities.…”

The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia

“…12,15,17,24,25 The reason for the high incidence of STAT3 mutations in Multiple STAT3 mutations in LGL leukemia haematologica | 2015; 100(1) LGL leukemia is unknown. In the detailed analysis of LGL populations, the occurrence of STAT3 mutations was restricted to expanded lymphocyte clones.…”

“…As an extreme example, two patients harbored four different STAT3 mutations (Figure 1). Patients with multiple STAT3 mutations could be divided into two different groups based on the allelic status derived from the amplicon data: (i) patients harboring two single nucleotide variants in the same STAT3 allele, resulting in one or two amino acid changes (n=4, Figure 1, patients 1-4), and (ii) patients displaying multiple STAT3 mutations in different alleles and lymphocyte clones (n=14, Figure 1, patients [5][6][7][8][9][10][11][12][13][14][15][16][17][18] …”

“…6,7 The importance of these pathways has been emphasized in the light of the recent discovery of somatic mutations in STAT3 and STAT5b genes. [8][9][10][11][12][13] The mutations were located in the Src-like homologue 2 (SH2) domain of STAT3 and STAT5b, caused constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT3 and STATb5 in vitro. 8,9,14 Expression of mutated STAT3 in mouse bone marrow led to the development of myeloproliferative neoplasm, and recently similar STAT3 and STAT5b mutations have also been discovered in other hematologic malignancies.…”

“…8,9,14 Expression of mutated STAT3 in mouse bone marrow led to the development of myeloproliferative neoplasm, and recently similar STAT3 and STAT5b mutations have also been discovered in other hematologic malignancies. 12,[15][16][17][18][19] In this project we aimed to analyze the frequency of STAT3 mutations and the clonal architecture of expanded lymphocytes using both STAT3 and TCR beta (TCRB) chain deep sequencing methods in a unique cohort of 213 patients with LGL leukemia. In addition, the effect of immunosuppressive treatment on the mutated clones was studied in follow-up samples obtained during therapy to assess if quantitative STAT3 mutation analysis could be used to monitor therapy response.…”