TY - JOUR
T1 - Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy
AU - Ganan-Gomez, Irene
AU - Yang, Hui
AU - Ma, Feiyang
AU - Montalban-Bravo, Guillermo
AU - Thongon, Natthakan
AU - Marchica, Valentina
AU - Richard-Carpentier, Guillaume
AU - Chien, Kelly
AU - Manyam, Ganiraju
AU - Wang, Feng
AU - Alfonso, Ana
AU - Chen, Shuaitong
AU - Class, Caleb
AU - Kanagal-Shamanna, Rashmi
AU - Ingram, Justin P.
AU - Ogoti, Yamini
AU - Rose, Ashley
AU - Loghavi, Sanam
AU - Lockyer, Pamela
AU - Cambo, Benedetta
AU - Muftuoglu, Muharrem
AU - Schneider, Sarah
AU - Adema, Vera
AU - McLellan, Michael
AU - Garza, John
AU - Marchesini, Matteo
AU - Giuliani, Nicola
AU - Pellegrini, Matteo
AU - Wang, Jing
AU - Walker, Jason
AU - Li, Ziyi
AU - Takahashi, Koichi
AU - Leverson, Joel D.
AU - Bueso-Ramos, Carlos
AU - Andreeff, Michael
AU - Clise-Dwyer, Karen
AU - Garcia-Manero, Guillermo
AU - Colla, Simona
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-022-01696-4
DO - 10.1038/s41591-022-01696-4
M3 - Article
C2 - 35241842
AN - SCOPUS:85125544660
SN - 1078-8956
VL - 28
SP - 557
EP - 567
JO - Nature medicine
JF - Nature medicine
IS - 3
ER -