STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

Abstract

Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs

Phosphorylated STAT3 expression in hematopoietic stem cell transplant-associated large granular lymphocytic leukemia

“…However, evidence of increased STAT3 activity has been shown in patients meeting strict criteria for LGL leukemia with both wild-type and mutated STAT3. 6-8 Jerez et al 7 showed that both cases of STAT3-mutated and wild-type LGL leukemia produce increased amounts of pSTAT3 and both types showed similar profiles of dysregulation in genes involved in apoptosis. Thus, other mechanisms of increased STAT3 activity in LGL leukemia may exist but likely confer similar features.…”

“…STAT3 mutation has been demonstrated in both T-cell and natural killer (NK) cell-derived cases, and is associated with increased phosphorylated STAT3 protein (pSTAT3) which can be visualized by immunohistochemistry (IHC). 6,7 Furthermore, increased pSTAT3 and STAT3 activity has been demonstrated in both STAT3-mutated and wild-type LGL leukemia when strict diagnostic criteria are used. 7 In order to better understand this rare disease, we used strict diagnostic criteria to identify seven patients who developed LGL leukemia following HSCT and used IHC to assess for nuclear localization of pSTAT3 in leukemic cells.…”

“…[5][6][7][8] However, studies evaluating this pathway in HSCT-associated cases are lacking. The mutation involves the Src homology 2 domain of the gene, which is responsible for dimerization and activation/phosphorylation of the STAT3 protein.…”

“…6,7 The retrospective nature of our study precluded us from analyzing our patient population for STAT3 mutation. However, evidence of increased STAT3 activity has been shown in patients meeting strict criteria for LGL leukemia with both wild-type and mutated STAT3.…”

“…There is evidence that STAT3 activation can help identify patients with LGL leukemia versus reactive LGL expansion. Jerez et al 7 used criteria similar to those we applied to identify 170 patients with LGL leukemia and 31 with neutropenia and circulating LGLs who did not meet their diagnostic criteria. STAT3 mutations were found only in the former group.…”