Identification of t(X;1)(q28;q21) generating a novel GATAD2B::MTCP1 gene fusion in CMML and its persistence during progression to AML

Hematological malignancies often involve chromosomal translocations and fusion genes that drive disease progression. While MTCP1 is well-known in T-cell prolymphocytic leukemia (T-PLL), its role in myeloid neoplasms is less understood. This report presents the first identification of the t(X;1)(q28;q21) translocation leading to the GATAD2B::MTCP1 fusion in acute myeloid leukemia (AML) transformed from chronic myelomonocytic leukemia (CMML). The karyotypes were described according to the International System for Human Cytogenetic Nomenclature 2009. We performed targeted next-generation sequencing (NGS) on a panel of 172 genes commonly mutated in hematological malignancies (Supplemental Table 1), using an Illumina platform. RNA sequencing was conducted on total RNA extracted from bone marrow, also using the Illumina platform. The GATAD2B::MTCP1 fusion gene was confirmed by reverse transcription-polymerase chain reaction (RT–PCR) and Sanger sequencing, with specific primers for the fusion transcript (GATAD2B-F: CCTCTTTTTTTCGACGCC; MTCP1-R: ACTGAGCACAACACTTACGC). The GATAD2B::MTCP1 fusion results from a breakpoint on 1q21 within GATAD2B exon 1 and Xq28 within MTCP1 exon 2. The patient with the GATAD2B::MTCP1 fusion exhibited disease progression from CMML to AML. Despite achieving initial remission with venetoclax-based therapy and allo-HSCT, the patient relapsed and died. We propose that the GATAD2B::MTCP1 fusion upregulates MTCP1 expression rather than generating a fusion protein, thereby contributing to transformation and relapse in AML. Further investigations are needed to elucidate the precise role of this fusion event in myeloid malignancies.

血液系统恶性肿瘤（Hematological malignancies）常伴随驱动疾病进展的染色体易位（chromosomal translocations）与融合基因（fusion genes）。MTCP1基因（MTCP1）在T细胞幼淋巴细胞白血病（T-cell prolymphocytic leukemia, T-PLL）中已被广泛认知，但其在髓系肿瘤（myeloid neoplasms）中的作用仍不甚明确。本研究首次鉴定出由t(X;1)(q28;q21)易位所导致的GATAD2B::MTCP1融合基因，该易位事件发生于由慢性粒单核细胞白血病（chronic myelomonocytic leukemia, CMML）转化而来的急性髓系白血病（acute myeloid leukemia, AML）病例中。核型分析按照《人类细胞遗传学命名国际体系2009版》（International System for Human Cytogenetic Nomenclature 2009）的标准进行描述。本研究采用Illumina测序平台（Illumina platform），针对血液系统恶性肿瘤中常见突变的172个基因（补充表1）开展靶向二代测序（next-generation sequencing, NGS）；同时使用该平台对骨髓提取的总RNA进行RNA测序（RNA sequencing）。通过针对融合转录本的特异性引物（GATAD2B-F: CCTCTTTTTTTCGACGCC；MTCP1-R: ACTGAGCACAACACTTACGC），结合逆转录聚合酶链反应（reverse transcription-polymerase chain reaction, RT-PCR）与Sanger测序（Sanger sequencing），证实了GATAD2B::MTCP1融合基因的存在。该融合基因源于1号染色体1q21区域内GATAD2B基因第1外显子与X染色体Xq28区域内MTCP1基因第2外显子的断点融合。携带该融合基因的患者出现了从CMML到AML的疾病进展。尽管患者在接受以维奈克拉（venetoclax）为基础的治疗及异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation, allo-HSCT）后获得了初始缓解，但最终仍复发并死亡。本研究推测，GATAD2B::MTCP1融合基因并非通过产生融合蛋白（fusion protein）发挥作用，而是通过上调MTCP1的表达，参与AML的疾病转化与复发过程。未来仍需开展进一步研究，以阐明该融合事件在髓系恶性肿瘤中的确切作用机制。