Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes

Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T. Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero and Simona Colla ()
Additional contact information
Juan Jose Rodriguez-Sevilla: The University of Texas MD Anderson Cancer Center
Irene Ganan-Gomez: The University of Texas MD Anderson Cancer Center
Feiyang Ma: University of California Los Angeles
Kelly Chien: The University of Texas MD Anderson Cancer Center
Monica Rey: University Hospital of Salamanca, IBSAL Cancer Center
Sanam Loghavi: The University of Texas MD Anderson Cancer Center
Guillermo Montalban-Bravo: The University of Texas MD Anderson Cancer Center
Vera Adema: The University of Texas MD Anderson Cancer Center
Bethany Wildeman: The University of Texas MD Anderson Cancer Center
Rashmi Kanagal-Shamanna: The University of Texas MD Anderson Cancer Center
Alexandre Bazinet: The University of Texas MD Anderson Cancer Center
Helen T. Chifotides: The University of Texas MD Anderson Cancer Center
Natthakan Thongon: The University of Texas MD Anderson Cancer Center
Xavier Calvo: Grup de Recerca Translacional en Neoplàsies Hematològiques (GRETNHE), Hospital del Mar Research Institute (IMIM)
Jesús María Hernández-Rivas: University Hospital of Salamanca, IBSAL Cancer Center
Maria Díez-Campelo: University Hospital of Salamanca, IBSAL Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Simona Colla: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-5

Abstract: Abstract The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs’ survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.

Date: 2024
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DOI: 10.1038/s41467-024-46424-3

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