Chromosome translocations in the 5q31-33 region are associated with a range of hematologic malignancies, some of which involve the platelet-derived growth factor receptor beta (PDGFRB) gene. We report a case of acute myeloid leukemia (AML) with a mutation in the NPM1 gene (NPM1-mut AML) and a subclonal gene rearrangement involving the PDGFRB gene. We identified a novel fusion gene, STRN3::PDGFRB, resulting from t(5;14) (q32;q12) chromosomal rearrangement. Sequential FISH confirmed that ~15% of leukemic cells carried the PDGFRB gene rearrangement, which suggests that STRN3::PDGFRB is a previously unreported fusion gene in a subclone. Reverse transcription PCR (RT-PCR) and Sanger sequencing confirmed that the fusion gene consisted of STRN3 exon 7 fused to PDGFRB exon 11, resulting in a chimeric protein containing the coiled-coil domain of striatin-3 and the transmembrane and intracellular tyrosine kinase domains of the PDGFRB. The new protein exhibited distinct cytoplasmic localization and had leukemogenic effects, as demonstrated by its ability to transform Ba/F3 cells to growth factor independence and cause a fatal myelodysplastic/myeloproliferative neoplasm (MDS/MPN)-like disease in mice, which then transformant to T-cell lymphoblastic lymphoma in secondary recipients. Ba/F3 cells expressing STRN3::PDGFRB or ETV6::PDGFRB were sensitive to tyrosine kinase inhibitors (TKIs) and selinexor, but in vitro experiments showed that the combination of imatinib and selinexor had a marked synergistic effect, although only the imatinib alone group could prolong the survival of T-cell blast transformation recipient mice. Our findings demonstrate the leukemogenic effects of the novel fusion gene and provide insights into the clone evolution of AML, which can be influenced by therapy selection. Furthermore, our results provide insight into the potential therapeutic options for patients with this type of mutation, as well as the need for careful consideration of treatment selection to prevent undesirable side effects.

5q31-33 区域的染色体易位与一系列血液恶性肿瘤相关，其中一些涉及血小板衍生生长因子受体 β ( PDGFRB ) 基因。我们报告了一例急性髓性白血病 (AML)，其NPM1基因发生突变 ( NPM1 -mut AML)，并且涉及PDGFRB基因的亚克隆基因重排。我们鉴定了一个新的融合基因STRN3::PDGFRB ，它是由 t(5;14) (q32;q12) 染色体重排产生的。连续 FISH 证实约 15% 的白血病细胞携带PDGFRB基因重排，这表明STRN3::PDGFRB是亚克隆中先前未报道的融合基因。逆转录PCR (RT-PCR) 和Sanger 测序证实融合基因由STRN3外显子7 与PDGFRB外显子11 融合组成，产生包含striatin-3 卷曲螺旋结构域以及跨膜和细胞内酪氨酸激酶结构域的嵌合蛋白PDGFRB 的。新蛋白表现出独特的细胞质定位并具有致白血病作用，其能够将 Ba/F3 细胞转化为生长因子独立性并在小鼠中引起致命的骨髓增生异常/骨髓增生性肿瘤 (MDS/MPN) 样疾病，然后转化为继发性受者中的 T 细胞淋巴母细胞淋巴瘤。表达STRN3::PDGFRB或ETV6::PDGFRB的Ba/F3细胞对酪氨酸激酶抑制剂（TKI）和selinexor敏感，但体外实验表明伊马替尼和selinexor联合具有明显的协同作用，尽管只有伊马替尼单独组可以延长T细胞母细胞转化受体小鼠的存活时间。 我们的研究结果证明了新型融合基因的致白血病作用，并为 AML 的克隆进化提供了见解，这可能会受到治疗选择的影响。此外，我们的结果让我们深入了解患有此类突变的患者的潜在治疗选择，以及仔细考虑治疗选择以防止不良副作用的必要性。