Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide

Guillermo Serrano, Nerea Berastegui, Aintzane Díaz-Mazkiaran, Paula García-Olloqui, Carmen Rodriguez-Res, Sofia Huerga-Dominguez, Marina Ainciburu, Amaia Vilas-Zornoza, Patxi San Martin-Uriz, Paula Aguirre-Ruiz, Asier Ullate-Agote, Beñat Ariceta, Jose-Maria Lamo-Espinosa, Pamela Acha, Oriol Calvete, Tamara Jimenez, Antonieta Molero, Maria Julia Montoro, Maria Díez-Campelo, David Valcarcel, Francisco Solé, Ana Alfonso-Pierola, Idoia Ochoa, Felipe Prósper (), Teresa Ezponda () and Mikel Hernaez ()
Additional contact information
Guillermo Serrano: Cancer Center Clínica Universidad de Navarra (CCUN), IdISNA
Nerea Berastegui: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Aintzane Díaz-Mazkiaran: Cancer Center Clínica Universidad de Navarra (CCUN), IdISNA
Paula García-Olloqui: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Carmen Rodriguez-Res: Cancer Center Clínica Universidad de Navarra (CCUN), IdISNA
Sofia Huerga-Dominguez: Cancer Center Clínica Universidad de Navarra (CCUN), IdISNA
Marina Ainciburu: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Amaia Vilas-Zornoza: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Patxi San Martin-Uriz: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Paula Aguirre-Ruiz: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Asier Ullate-Agote: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Beñat Ariceta: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Jose-Maria Lamo-Espinosa: Clínica Universidad de Navarra
Pamela Acha: Universitat Autònoma de Barcelona
Oriol Calvete: Universitat Autònoma de Barcelona
Tamara Jimenez: CIBERONC
Antonieta Molero: Hospital Universitari Vall d’Hebron, Barcelona; Vall d’Hebron Instituto de Oncología (VHIO)
Maria Julia Montoro: Hospital Universitari Vall d’Hebron, Barcelona; Vall d’Hebron Instituto de Oncología (VHIO)
Maria Díez-Campelo: CIBERONC
David Valcarcel: Hospital Universitari Vall d’Hebron, Barcelona; Vall d’Hebron Instituto de Oncología (VHIO)
Francisco Solé: Universitat Autònoma de Barcelona
Ana Alfonso-Pierola: CIBERONC
Idoia Ochoa: University of Navarra
Felipe Prósper: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Teresa Ezponda: Cancer Center Clínica Universidad de Navarra (CCUN), IdiSNA
Mikel Hernaez: Cancer Center Clínica Universidad de Navarra (CCUN), IdISNA

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.

Date: 2024
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DOI: 10.1038/s41467-024-49529-x

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