Multiomics of three distinct hematological malignancies in a patient reveals their common origin from clonal hematopoietic stem cells

Concomitant multiple hematological malignancies are rare and challenging to diagnose. They represent a unique model to explore the multistep process of oncogenesis. Here, we report the unique case of 62 years-old man with cardiac tamponade as first manifestation of ALK negative anaplastic large T-cell lymphoma (ALK- ALCL). Following chemotherapy, he showed one year later ALK- ALCL concurrent with diffuse large B-cell lymphoma (DLBCL-NOS) and acute monoblastic leukemia (AML-M5) in a single excisional lymph node. Clinical, pathological and multiomics data (whole exome and targeted deep sequencing, spatial transcriptomics) were analyzed. Two somatic TET2 gene mutations at high allele burden were shared by all three neoplasms, uninvolved bone marrow and CD34+ hematopoietic stem and progenitor cells (HSPCs). Secondary hits characterized each malignancy. ALK- ALCL (pericardial and nodal) showed TP53 and LYN deleterious mutations, DLBCL-NOS disclosed KRAS, STAT6, CREBBP and ATM alterations and AML-M5 had JAK3, PPM1D, NF1 and KMT2D mutations and a complex karyotype. Furthermore we demonstrated that spatial transcriptomics can identify the specific signatures of the three neoplasms. Two TET2 mutations at high allele burden in CD34+HSPCs conferred the favorable soil and the genotoxic stress from chemotherapy likely contributed to multiple hematological malignancies oncogenesis. Our case confirms the pathogenetic link between clonal hematopoiesis and cytotoxic T-cell lymphoma, so far only suspected. Most importantly, this is the first study to document the oncogenic phylogeny of concurrent T-, B-, and myeloid neoplasms from CD34+ HSPCs clone(s) in a single specimen.

伴随性多发血液系统恶性肿瘤较为罕见且诊断难度极大，其为探究肿瘤发生的多步骤进程提供了独特的研究模型。本文报告1例62岁男性患者，以心脏压塞为首发表现的ALK阴性间变性大T细胞淋巴瘤（ALK- ALCL）。化疗后1年，患者单一切除淋巴结中同时出现ALK- ALCL、弥漫性大B细胞淋巴瘤（DLBCL-NOS）及急性单核细胞白血病（AML-M5）。研究对患者的临床、病理及多组学数据（全外显子组测序、靶向深度测序、空间转录组学）进行了分析。所有3种肿瘤、未受累骨髓及CD34+造血干祖细胞（HSPCs）均携带2种高等位基因负荷的体细胞TET2基因突变，而每种恶性肿瘤又各有其特异性的二次打击突变特征。ALK- ALCL（心包及淋巴结型）携带TP53与LYN有害突变，弥漫性大B细胞淋巴瘤（DLBCL-NOS）存在KRAS、STAT6、CREBBP及ATM变异，急性单核细胞白血病（AML-M5）则检出JAK3、PPM1D、NF1及KMT2D突变，且伴有复杂核型。此外，本研究证实空间转录组学可识别3种肿瘤的特异性特征。CD34+造血干祖细胞中2种高等位基因负荷的TET2突变构建了有利的“土壤”环境，而化疗带来的基因毒性应激可能促成了多发血液系统恶性肿瘤的发生。本病例证实了克隆性造血与细胞毒性T细胞淋巴瘤之间的致病关联——这一关联此前仅为推测。尤为重要的是，本研究首次在单一标本中揭示了源自CD34+造血干祖细胞克隆的T细胞、B细胞及髓系肿瘤同时发生的致癌系统发育关系。