Clonal cytopenia of undetermined significance (CCUS)-associated reversion of donor-derived, transient αβ T-cell large granular clonal lymphocytosis, emerging post-transplant in a patient with a history of γδ T-cell large granular lymphocytic leukemia.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2023-04-01 DOI:10.1101/mcs.a006241
Siba El Hussein, Andrew G Evans, John M Fitzsimmons, Nufatt Leong, Meghan Buldo, Jeremy P Segal, Audrey N Jajosky, Paul G Rothberg, Jane L Liesveld, Zoltán N Oltvai
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Abstract

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a case of donor-derived, transient Alpha Beta (αβ) T-cell large granular clonal lymphocytosis and cytopenia that emerged post-HSCT in a patient with a history of gamma delta (γδ) T-cell large granular lymphocytic leukemia (T-LGLL). Clonal unrelatedness of post-transplant T-LGL lymphocytosis to the patient's pretransplant T-LGLL was first identified by T-cell receptor (TCR) PCR showing different sized fragments of rearranged gamma chains, in addition to shift from γδ to αβ TCR expression by flow cytometry analyses. Donor-derivation of the patient's post-transplant clonal lymphocytosis was confirmed by serial chimerism analyses of recipient's blood specimens demonstrating 100% donor DNA. Moreover, oncogenic DNMT3A and RUNX1 mutations were detected by next-generation sequencing (NGS) only in post-transplant specimens. Intriguingly, despite continued increase in DNMT3A and RUNX1 mutation load, the patient's clonal lymphocytosis and anemia eventually largely resolved; yet, the observed mutation profile with persistent thrombocytopenia indicated secondary clonal cytopenia of undetermined significance (CCUS) in the absence of overt morphologic evidence of myeloid neoplasm in the marrow. This case illustrates the utility of longitudinal chimerism analysis and NGS testing combined with flow cytometric immunophenotyping to evaluate emerging donor-derived hematolymphoid processes and to properly interpret partial functional engraftment. It may also support the notion that driver mutation-induced microenvironmental changes may paradoxically contribute to reestablishing tissue homeostasis.

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一名有γδ t细胞大颗粒淋巴细胞白血病病史的患者在移植后出现供体来源的短暂性αβ t细胞大颗粒克隆性淋巴细胞增多症(CCUS)相关逆转。
自体和异体造血干细胞移植(HSCT)已经彻底改变了淋巴细胞恶性肿瘤的治疗。然而,如何最好地检测或预测hsct相关并发症的出现仍然没有解决。在这里,我们描述了一例供体来源的,短暂的αβ (αβ) t细胞大颗粒克隆性淋巴细胞增多症和细胞减少症,发生在有γδ (γδ) t细胞大颗粒淋巴细胞白血病(T-LGLL)病史的患者的hsct后。移植后T-LGL淋巴细胞增多与患者移植前T-LGL的克隆不相关性首次通过t细胞受体(TCR) PCR鉴定,显示出不同大小的重排γ链片段,流式细胞术分析显示,TCR的表达从γδ转变为αβ。患者移植后克隆性淋巴细胞增多症的供体来源通过受体血液标本的序列嵌合分析得到证实,显示100%的供体DNA。此外,仅在移植后标本中通过下一代测序(NGS)检测到致癌DNMT3A和RUNX1突变。有趣的是,尽管DNMT3A和RUNX1突变负荷持续增加,但患者的克隆性淋巴细胞增多症和贫血最终在很大程度上得到解决;然而,观察到的持续性血小板减少症的突变谱表明,在骨髓中没有明显的髓系肿瘤的形态学证据的情况下,继发性克隆性细胞减少症具有不确定的意义(CCUS)。该病例说明了纵向嵌合分析和NGS检测结合流式细胞免疫分型来评估新出现的供体源性血淋巴过程和正确解释部分功能植入的有效性。这也可能支持这样一种观点,即驱动突变诱导的微环境变化可能矛盾地有助于重建组织稳态。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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