Primary myelofibrosis (PMF) patients frequently have JAK2 (V617F), CALR (exon 9), or MPL (W515 or exon 10) strong driver gene mutation, which triggers abnormal activation of the JAK2-STATs signaling pathway that plays a complex role in the occurrence of PMF. However, about 10–15% of PMF patients have no above typical mutations in these strong driver genes, known as being “triple-negative”, which are associated with poor prognosis. In this paper, we reported a unique secondary acute myeloid leukemia (sAML) case transformed from triple-negative PMF combined with lung cancer and erythroderma occurrence at the same time, which has not been reported so far. Through whole blood exome sequencing, four novel noncanonical mutations were detected in key regulatory genes SH2B3 (Q748 and S710) and STAT5a (C350 and K354). Meanwhile, STAT5a-S710 and SH2B3-K354 noncanonical mutations gained strong malignant biofunction on promoting cell growth and tumorigenesis by accelerating the G1/S transition. In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).

原发性骨髓纤维化 (PMF) 患者经常存在JAK2 (V617F)、CALR（外显子 9）或MPL（W515 或外显子 10）强驱动基因突变，这会触发 JAK2-STATs 信号通路的异常激活，该通路在骨髓纤维化中发挥着复杂的作用。 PMF 的发生。然而，约 10-15% 的 PMF 患者在这些强驱动基因中没有以上典型的突变，即所谓的“三阴性”，这与不良预后相关。本文报道了一例独特的由三阴性PMF转化而来的继发性急性髓系白血病（sAML）并同时发生肺癌和红皮病的病例，迄今为止尚未见报道。通过全血外显子组测序，在关键调控基因SH2B 3（Q748和S710）和STAT5a（C350和K354 ）中检测到四种新的非典型突变。同时，STAT5a-S710和SH2B3-K354非典型突变通过加速G1/S转变获得了促进细胞生长和肿瘤发生的强大恶性生物功能。在机制研究中，这些由非典型突变驱动的有害表型可能是通过激活 p-STAT5a/c-Myc/CyclinD1 和 p-STAT3/p-AKT/p-ERK1/2 信号轴而引发的初始 PMF。因此，我们的研究探讨了STAT5a和SH2B3中新型非典型突变的有害作用，这些突变可能作为易感基因，并在 PMF 发展为急性髓系白血病-M2a (AML-M2a) 的过程中表现出致癌生物功能。