Publicaciones científicas
Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes
Irene Ganan-Gomez 1, Hui Yang 1, Feiyang Ma 2 3, Guillermo Montalban-Bravo 1, Natthakan Thongon 1, Valentina Marchica 4, Guillaume Richard-Carpentier 1, Kelly Chien 1, Ganiraju Manyam 5, Feng Wang 6, Ana Alfonso 1, Shuaitong Chen 1, Caleb Class 7, Rashmi Kanagal-Shamanna 8, Justin P Ingram 9, Yamini Ogoti 1, Ashley Rose 1, Sanam Loghavi 8, Pamela Lockyer 1, Benedetta Cambo 4, Muharrem Muftuoglu 1, Sarah Schneider 10, Vera Adema 1, Michael McLellan 11, John Garza 11, Matteo Marchesini 1 12, Nicola Giuliani 4, Matteo Pellegrini 2, Jing Wang 5, Jason Walker 11, Ziyi Li 7, Koichi Takahashi 1, Joel D Leverson 9, Carlos Bueso-Ramos 8, Michael Andreeff 1, Karen Clise-Dwyer 10, Guillermo Garcia-Manero 1, Simona Colla 13
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.
CITA DEL ARTÍCULO Nat Med. 2022 Mar;28(3):557-567. doi: 10.1038/s41591-022-01696-4. Epub 2022 Mar 3.
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