Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2024 Oct 15;30(20):4681-4689. doi: 10.1158/1078-0432.CCR-24-0066.
STAT3 is a key transcription factor that mediates cancer progression through phosphorylation or gain-of-function mutations. STAT3 activation in myeloid neoplasms (MN) is primarily mediated through phosphorylation. STAT3 mutation has only rarely been reported in MNs.
We assessed the clinicopathologic and molecular genetic features of 32 STAT3-mutated MNs.
The frequency of STAT3 mutation in MNs was <0.5%. Twenty (62.5%) cases were classified as acute myeloid leukemia, 7 (21.9%) as myelodysplastic syndrome, and 5 (15.6%) as chronic myelomonocytic leukemia, but none as myeloproliferative neoplasms. STAT3 mutations occurred at initial diagnosis in 22 (88%) cases or at relapse or upon leukemic transformation. Clonal hierarchy analysis revealed that STAT3 mutations represented the dominant clone in 30% of acute myeloid leukemia cases but were subclonal in myelodysplastic syndrome and chronic myelomonocytic leukemia. Most were missense mutations located at the SH2 domain, Y640F being the most common. STAT3 mutation was accompanied by coexisting mutations in all cases, most frequently SRSF2, TET2, ASXL1, and SETBP1. STAT3 mutations were usually associated with morphologic dysplasia, increased blasts, and monosomy 7/del7q. With a median follow-up of 24.5 months, 21 patients died, 6 had persistent disease, and 5 achieved complete remission after stem cell transplantation.
STAT3 mutation is present in various MNs but not in myeloproliferative neoplasms. It is often an early event or occurs upon leukemic transformation, which suggests an important role in the pathogenesis and progression of MNs by activating the JAK-STAT pathway. It may help determine a subset of patients with MNs who may benefit from targeted therapy. See related commentary by Hochman and Frank, p. 4554.
STAT3 是一种关键的转录因子，通过磷酸化或获得功能突变介导癌症进展。髓系肿瘤（MN）中 STAT3 的激活主要通过磷酸化介导。STAT3 突变在 MN 中很少见报道。
我们评估了 32 例 STAT3 突变 MN 的临床病理和分子遗传学特征。
MN 中 STAT3 突变的频率<0.5%。20 例（62.5%）病例被归类为急性髓系白血病，7 例（21.9%）为骨髓增生异常综合征，5 例（15.6%）为慢性粒单核细胞白血病，但均无骨髓增殖性肿瘤。STAT3 突变发生在 22 例（88%）病例的初诊时或在复发或白血病转化时。克隆层次分析显示，STAT3 突变在 30%的急性髓系白血病病例中代表优势克隆，但在骨髓增生异常综合征和慢性粒单核细胞白血病中为亚克隆。大多数是位于 SH2 结构域的错义突变，其中 Y640F 最为常见。所有病例均伴有共存突变，最常见的是 SRSF2、TET2、ASXL1 和 SETBP1。STAT3 突变通常与形态学发育不良、增加的原始细胞和单体 7/缺失 7q 相关。中位随访 24.5 个月后，21 例患者死亡，6 例患者疾病持续存在，5 例患者在干细胞移植后完全缓解。
STAT3 突变存在于各种 MN 中，但不存在于骨髓增殖性肿瘤中。它通常是早期事件或在白血病转化时发生，这表明它通过激活 JAK-STAT 通路在 MN 的发病机制和进展中起着重要作用。它可能有助于确定一组可能受益于靶向治疗的 MN 患者。有关 Hochman 和 Frank 的相关评论，请见第 4554 页。
