Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes

Elena Martínez-Balsalobre, Jesús García-Castillo, Diana García-Moreno, Elena Naranjo-Sánchez, Miriam Fernández-Lajarín, María A. Blasco, Francisca Alcaraz-Pérez (), Victoriano Mulero () and María L. Cayuela ()
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Elena Martínez-Balsalobre: Hospital Clínico Universitario Virgen de la Arrixaca
Jesús García-Castillo: Hospital Clínico Universitario Virgen de la Arrixaca
Diana García-Moreno: Hospital Clínico Universitario Virgen de la Arrixaca
Elena Naranjo-Sánchez: Hospital Clínico Universitario Virgen de la Arrixaca
Miriam Fernández-Lajarín: Hospital Clínico Universitario Virgen de la Arrixaca
María A. Blasco: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO)
Francisca Alcaraz-Pérez: Hospital Clínico Universitario Virgen de la Arrixaca
Victoriano Mulero: Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla
María L. Cayuela: Hospital Clínico Universitario Virgen de la Arrixaca

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.

Date: 2023
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DOI: 10.1038/s41467-023-41472-7

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