Bone marrow niches in haematological malignancies.
Bone marrow niches in haematological malignancies.
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DOI：
10.1038/s41568-020-0245-2
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发表时间：
2020-05
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--
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血液系统恶性肿瘤以前被认为是由造血细胞内的遗传或表观遗传病变单独驱动的。然而，维持和调节血液和免疫细胞的日常生产的小生境现在越来越多地被认为在血液恶性肿瘤的发病机制和耐药性中具有重要作用。在造血细胞内，少量复发突变的积累会引发恶性肿瘤。同时，支持造血干细胞及其后代的小生境的特定改变可以作为易感事件，促进突变造血细胞存活和扩增，以及促进恶性肿瘤进展和保护恶性肿瘤细胞免受化疗，最终导致复发。在这篇透视文章中，我们总结了我们目前对健康和疾病期间骨髓（BM）专门造血小生境的组成和功能的理解。我们讨论的疾病机制（而不是恶性亚型），以提供一个全面的描述，在多种血液系统恶性肿瘤共享的关键生态位相关的途径。这些机制包括骨髓小生境细胞中的主要驱动突变，与缺氧增加相关的变化，血管生成和炎症以及基质小生境细胞的代谢重编程。因此，骨髓小生境的重塑可以促进免疫逃避和存活途径的激活，从而有利于恶性造血细胞的维持、防御过量的活性氧（ROS）和保护免受化疗。最后，我们建议患者样本的处理和生物库以及利基分析的指导方针，以确保确定治疗靶点的基础研究可以更有效地转化为临床。希望是将骨髓小生境如何有助于血液病易感性，启动，进展和对治疗的反应的知识整合到未来的临床实践中，可能会改善这些疾病的治疗。该观点概述了我们目前对骨髓生态位如何促进血液系统恶性肿瘤的发生和进展的了解，并提出了该领域的指导方针，这可能有助于克服现有的研究挑战。
Haematological malignancies were previously thought to be driven solely by genetic or epigenetic lesions within haematopoietic cells. However, the niches which maintain and regulate daily production of blood and immune cells are now increasingly being recognised as having an important role in the pathogenesis and chemoresistance of haematological malignancies. Within haematopoietic cells, the accumulation of a small number of recurrent mutations initiates malignancy. Concomitantly, specific alterations of the niches, which support haematopoietic stem cells and their progeny, can act as predisposition events, facilitating mutant haematopoietic cell survival and expansion as well as contributing to malignancy progression and providing protection of malignant cells from chemotherapy, ultimately leading to relapse. In this Perspective article, we summarise our current understanding of the composition and function of the specialised haematopoietic niches of the bone marrow (BM) during health and disease. We discuss disease mechanisms (rather than malignancy subtypes) to provide a comprehensive description of key niche-associated pathways that are shared across multiple haematological malignancies. These mechanisms include primary driver mutations in bone marrow niche cells, changes associated with increased hypoxia, angiogenesis and inflammation as well as metabolic reprogramming by stromal niche cells. Consequently, remodelling of bone marrow niches can facilitate immune evasion and activation of survival pathways favouring malignant haematopoietic cell maintenance, defence against excessive reactive oxygen species (ROS) and protection from chemotherapy. Lastly, we suggest guidelines for the handling and biobanking of patient samples and analysis of the niche to ensure that basic research identifying therapeutic targets can be more efficiently translated to the clinic. The hope is that integrating knowledge of how bone marrow niches contribute to haematological disease predisposition, initiation, progression and response to therapy into future clinical practice will likely improve the treatment of these disorders. This Perspective outlines our current understanding of how the bone marrow niche contributes to both the initiation and progression of haematological malignancies and suggests guidelines for the field which might help to overcome existing research challenges.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
--
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Boutter J;Huang Y;Marovca B;Vonderheit A;Grotzer MA;Eckert C;Cario G;Wollscheid B;Horvath P;Bornhauser BC;Bourquin JP
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Bourquin JP
在健康个体中预测急性髓样白血病的风险。
影响因子：
64.8
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Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
通讯作者：
Shlush LI
影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
21.3
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Asada N;Kunisaki Y;Pierce H;Wang Z;Fernandez NF;Birbrair A;Ma'ayan A;Frenette PS
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Frenette PS