小柯机器人

美国德克萨斯大学Simona Colla团队发现，干细胞结构驱动骨髓增生异常综合征进展并预测对venetoclax治疗的反应。2022年3月3日，国际知名学术期刊《自然—医学》在线发表了这一成果。

Author: Ganan-Gomez, Irene, Yang, Hui, Ma, Feiyang, Montalban-Bravo, Guillermo, Thongon, Natthakan, Marchica, Valentina, Richard-Carpentier, Guillaume, Chien, Kelly, Manyam, Ganiraju, Wang, Feng, Alfonso, Ana, Chen, Shuaitong, Class, Caleb, Kanagal-Shamanna, Rashmi, Ingram, Justin P., Ogoti, Yamini, Rose, Ashley, Loghavi, Sanam, Lockyer, Pamela, Cambo, Benedetta, Muftuoglu, Muharrem, Schneider, Sarah, Adema, Vera, McLellan, Michael, Garza, John, Marchesini, Matteo, Giuliani, Nicola, Pellegrini, Matteo, Wang, Jing, Walker, Jason, Li, Ziyi, Takahashi, Koichi, Leverson, Joel D., Bueso-Ramos, Carlos, Andreeff, Michael, Clise-Dwyer, Karen, Garcia-Manero, Guillermo, Colla, Simona

Issue&Volume: 2022-03-03

Abstract: Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS. Extensive characterization of the stem and progenitor cell hierarchies of myelodysplastic syndromes reveals compensatory survival mechanisms underpinning the failure of hypomethylating agents, and uncovers biomarkers that predict second-line clinical response to venetoclax-based therapy.

DOI: 10.1038/s41591-022-01696-4

Source: https://www.nature.com/articles/s41591-022-01696-4

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex