Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.
Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.
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单细胞转录本揭示了KMT2A重排婴儿B细胞急性淋巴细胞性白血病独特的发育状态。
DOI：
10.1038/s41591-022-01720-7
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发表时间：
2022-04
期刊：
影响因子：
82.9
通讯作者：
Behjati, Sam
中科院分区：
文献类型：
--
作者：
Khabirova, Eleonora;Jardine, Laura;Coorens, Tim H. H.;Webb, Simone;Treger, Taryn D.;Engelbert, Justin;Porter, Tarryn;Prigmore, Elena;Collord, Grace;Piapi, Alice;Teichmann, Sarah A.;Inglott, Sarah;Williams, Owen;Heidenreich, Olaf;Young, Matthew D.;Straathof, Karin;Bomken, Simon;Bartram, Jack;Haniffa, Muzlifah;Behjati, Sam
kmt2a重排婴儿ALL是一种预后不良的侵袭性儿童白血病。在这里，我们研究了kmt2a重排的婴儿b细胞急性淋巴细胞白血病（B-ALL）的发育状态，使用大量信使RNA （mRNA）荟萃分析和单个淋巴母细胞转录组对发育中的骨髓参考的检查。kmt2a重排的婴儿B-ALL独特地以早期淋巴细胞前体（ELP）状态为主，而不良程度较低的nutm1重排婴儿ALL表现出较晚发育的B细胞信号，与大多数其他儿童B-ALL一致。我们将婴儿淋巴母细胞与ELP细胞进行了比较，发现癌症具有骨髓-淋巴混合特征，包括非生生性抗原组合，可能达到癌症特异性。我们通过流式细胞术验证了样品组合的表面共表达。通过对一名婴儿KMT2A重排B-ALL复发为AML的儿童的不同白血病的共有突变的分析，我们确定KMT2A重排发生在非常早期的发育中，在造血分化之前，强调不能从转录状态推断细胞的起源。单细胞转录组学和系统发育分析揭示了婴儿b细胞急性淋巴细胞白血病的发展起源和潜在治疗靶点的新见解。
KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state. Single-cell transcriptomic and phylogenetic analyses reveal new insights into the developmental origin and potential therapeutic targets for a particularly aggressive form of B-cell acute lymphoblastic leukemia in infants.
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影响因子：
12.3
作者：
Buels R;Yao E;Diesh CM;Hayes RD;Munoz-Torres M;Helt G;Goodstein DM;Elsik CG;Lewis SE;Stein L;Holmes IH
通讯作者：
Holmes IH
影响因子：
12.8
作者：
Bassan R;Pavoni C;Intermesoli T;Spinelli O;Tosi M;Audisio E;Marmont F;Cattaneo C;Borlenghi E;Cortelazzo S;Cavattoni I;Fumagalli M;Mattei D;Romani C;Cortelezzi A;Fracchiolla N;Ciceri F;Bernardi M;Scattolin AM;Depaoli L;Masciulli A;Oldani E;Rambaldi A
通讯作者：
Rambaldi A
影响因子：
64.8
作者：
Jardine L;Webb S;Goh I;Quiroga Londoño M;Reynolds G;Mather M;Olabi B;Stephenson E;Botting RA;Horsfall D;Engelbert J;Maunder D;Mende N;Murnane C;Dann E;McGrath J;King H;Kucinski I;Queen R;Carey CD;Shrubsole C;Poyner E;Acres M;Jones C;Ness T;Coulthard R;Elliott N;O'Byrne S;Haltalli MLR;Lawrence JE;Lisgo S;Balogh P;Meyer KB;Prigmore E;Ambridge K;Jain MS;Efremova M;Pickard K;Creasey T;Bacardit J;Henderson D;Coxhead J;Filby A;Hussain R;Dixon D;McDonald D;Popescu DM;Kowalczyk MS;Li B;Ashenberg O;Tabaka M;Dionne D;Tickle TL;Slyper M;Rozenblatt-Rosen O;Regev A;Behjati S;Laurenti E;Wilson NK;Roy A;Göttgens B;Roberts I;Teichmann SA;Haniffa M
通讯作者：
Haniffa M
影响因子：
64.8
作者：
Coorens THH;Oliver TRW;Sanghvi R;Sovio U;Cook E;Vento-Tormo R;Haniffa M;Young MD;Rahbari R;Sebire N;Campbell PJ;Charnock-Jones DS;Smith GCS;Behjati S
通讯作者：
Behjati S
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.