Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.

尽管多种遗传事件被认为在促进骨髓增生性肿瘤 （MPN） 的进展中发挥作用，但与更具侵袭性的疾病表型的发展相关的单个事件仍然不明确。在这里，我们报道了染色体 12q14.3 的新基因组缺失，通过高分辨率阵列比较基因组杂交加单核苷酸多态性平台检测到，发生在 11% 的骨髓纤维化 （MF） 和 MPN 加速/急变期 （AP/BP） 的 MPN 患者中，但在真性红细胞增多症或原发性血小板增多症患者中未检测到。这些 12q14.3 缺失导致外显子 5 的大部分非编码区丢失，并在高迁移率组 AT 钩 2 （HMGA2） 的 3'UTR 中MIRLET7结合位点丢失，从而负向调节 HMGA2 表达。这些获得性 12q14.3 缺失主要在具有 CALR 和 ASXL1 共突变的 MF 患者中检测到，并导致更大程度的 HMGA2 转录本过表达，与存在 ASXL1 突变无关。涉及 HMGA2 的 12q 结构异常患者表现出更具侵袭性的临床病程，MPN-AP/BP 演变的频率更高。这些发现表明，与其 3'UTR 区基因组缺失相关的 HMGA2 过表达是一种新发现的遗传事件，有助于 MPN 进展。