Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy

Nat Med. 2022 Mar;28(3):557-567. doi: 10.1038/s41591-022-01696-4. | PubMed

Irene Ganan-Gomez¹, Hui Yang¹, Feiyang Ma^2,3, Guillermo Montalban-Bravo¹, Natthakan Thongon¹, Valentina Marchica⁴, Guillaume Richard-Carpentier¹, Kelly Chien¹, Ganiraju Manyam⁵, Feng Wang⁶, Ana Alfonso¹, Shuaitong Chen¹, Caleb Class⁷, Rashmi Kanagal-Shamanna⁸, Justin P Ingram⁹, Yamini Ogoti¹, Ashley Rose¹, Sanam Loghavi⁸, Pamela Lockyer¹, Benedetta Cambo⁴, Muharrem Muftuoglu¹, Sarah Schneider¹⁰, Vera Adema¹, Michael McLellan¹¹, John Garza¹¹, Matteo Marchesini^1,12, Nicola Giuliani⁴, Matteo Pellegrini², Jing Wang⁵, Jason Walker¹¹, Ziyi Li⁷, Koichi Takahashi¹, Joel D Leverson⁹, Carlos Bueso-Ramos⁸, Michael Andreeff¹, Karen Clise-Dwyer¹⁰, Guillermo Garcia-Manero¹, Simona Colla¹³

1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
3. Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
4. Department of Medicine and Surgery, University of Parma, Parma, Italy.
5. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9. AbbVie Oncology Discovery, Chicago, IL, USA.
10. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
11. McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
12. Istituto Romagnolo per lo Studio dei Tumori 'Dino Amadori', Meldola, Italy.
13. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. scolla@mdanderson.org.

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.

Presented By Irene Ganan-Gomez | ORCID iD