Frequent STAT3 mutations in CD8+ T cells from patients with pure red cell aplasia

Abstract

Dysregulation of T-cell–mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA–paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation–positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder–associated, and T-LGLL–associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation–positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation–negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.

<p>Pathophysiologic Mechanisms And Management Of Large Granular Lymphocytic Leukemia Associated Pure Red Cell Aplasia</p>

“…STAT3 mutations were found in 5 of 15 patients with idiopathic PRCA (33%), and 10 of 13 patients with T-LGLL-associated PRCA (77%) 18. Among the PRCA patients, 3 of the 29 PRCA patients without T-LGLL and 6 of the 13 PRCA patients with T-LGLL were positive for STAT3 mutations 59. These results suggested that the STAT3 mutations were limited to PRCA patients with or without T-LGLL.…”

“…Comparing STAT3 mutation(+) LGLL-associated PRCA patients with STAT3 mutation(-) patients, the STAT3 mutation(+) patients had more lymphocytes, more CD8+ T cells59 and showed a trend towards a younger age (median age, 52.5 years old and 77.5 years old) than the STAT3 mutation(-) patients 31. LGLL-associated PRCA patients showed a higher frequency of T-cell clonality and STAT3 mutations than PRCA patients without T-LGLL 59…”

“…T-LGLL is most frequent in LGLL-associated PRCA, and has been reported in case report or case series 6,9,10,12,16,18,59,64,71. These LGL expansions have been defined as neoplastic processes because of their clonal nature.…”

“…ORR was better in non-LGLL vs LGLL-assosicated PRCA (84% vs. 55%, P=0.01) 18. Kawakami T et al reported that the response rate to CsA in the STAT3 mutation(+) PRCA patients was significantly lower than that in the STAT3 mutation(-) patients (46% [6 of 13] vs 100% [8 of 8]) 59. Two STAT3 mutation(+) patients acquired resistance to CsA, whereas 8 STAT3 mutation(-) patients remained responsive to CsA.…”

“…Gene signature and mutational profiling may be an effective tool in determining what an appropriate treatment is. Patients with STAT3 mutations also tended to need more treatments 59. In LGLL-associated PRCA patients with STAT3 mutation, STAT3 activation led to multiple gene deregulations and treatment with STAT3 inhibitors induced the apoptosis of leukemic cells 56.…”