Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.,Leukemia

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Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.
Leukemia ( IF 12.8 ) Pub Date : 2019-11-27 , DOI: 10.1038/s41375-019-0662-y
Aurélie Caye _{1,

2} , Kevin Rouault-Pierre _{3,

4} , Marion Strullu _{1,

2} , Elodie Lainey _{1,

5} , Ander Abarrategi ₃ , Odile Fenneteau ₅ , Chloé Arfeuille _{1,

2} , Jennifer Osman _{1,

2} , Bruno Cassinat _{1,

6} , Sabrina Pereira ₂ , Fernando Anjos-Afonso ₃ , Erin Currie ₃ , Linda Ariza-McNaughton ₃ , Vincent Barlogis ₇ , Jean-Hugues Dalle ₈ , André Baruchel ₈ , Christine Chomienne _{1,

6} , Hélène Cavé _{1,

2} , Dominique Bonnet ₃

Affiliation

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.

中文翻译：

尽管造血干细胞发生突变，但 JMML 增殖细胞并不总是局限于此区室。

幼年型粒单核细胞白血病 (JMML) 是一种罕见的儿童早期侵袭性骨髓增生异常/骨髓增殖性肿瘤，由 RAS 激活突变引发。基因组分析最近描述了 JMML 突变景观；然而，JMML 增殖细胞 (JMML-PC) 的性质和该疾病的克隆结构至今仍难以捉摸。结合基因组（外显子组、RNA-seq）、集落形成测定和异种移植研究，我们检测到 JMML-PC 的存在，它忠实地再现了 JMML 特征，包括在诊断和复发时显性/次要克隆的复杂/非线性组织。进一步的综合分析还表明，尽管突变是在造血干细胞中获得的，但 JMML-PC 并不总是局限于此区室，这凸显了疾病在起始步骤中的异质性。我们发现，尽管部分患者中 CD90/THY-1 过度表达，但 JMML 中造血干/祖细胞表型总体保持不变。这项研究为 JMML 的个体发育和 JMML-PC 的身份提供了新的线索，并提供了强大的模型来监测疾病和测试新的治疗方法。

更新日期：2019-11-28

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