Ayala, R. (Rosa)

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    Biallelic TET2 mutations confer sensitivity to 5 '-azacitidine in acute myeloid leukemia
    (2023) Haferlach, T. (Torsten); Blair, H. (Helen); Martínez-López, J. (Joaquín); Ariceta, B. (Beñat); Ruhnke, L. (Leo); Soura, E.N. (Emmanouela-Niki); Bornhauser, M. (Martin); Wagenführ, L. (Lisa); Onel, K. (Kenan); Montesinos, P. (Pau); Nandana, D. (Devi); Meggendorfer, M. (Manja); Jackson, G.H. (Graham H.); Mohr, B. (Brigitte); Villar-Fernández, S. (Sara); Stölzel, F. (Friedrich); Marr, H.J. (Helen J.); Ayala, R. (Rosa); Jones, G.L. (Gail L.); Robinson, A. (Amber); Kunadt, D. (Desiree); Allan, J.M. (James M.); Menne, T. (Tobias); Wobus, M. (Manja); Elstob, C. (Claire); Altmann, H. (Heidi); Dill, C. (Claudia); Park, C. (Catherine); Fordham, S.E. (Sarah E.); Bziuk, Z. (Zuzanna); Wu, L.F. (Lani F.); Bowes, E. (Emily); Allsop, D. (Daniel); Alharbi, A. (Abrar); Piddock, R. (Rachel); Bell, H.L. (Hayden L.); Fadly, M. (Mohd); Prosper-Cardoso, F. (Felipe); Röllig, C. (Christoph); Heidenreich, O. (Olaf); Lin, W.Y. (Wei-Yu); Altschuler, S.J. (Steven J.); Rahman, T. (Thahira); Fitzgibbon, J. (Jude)
    Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5 '-azacitidine (5 '-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5 '-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5 '-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
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    Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project
    (2021) García-Boyero, R. (Raimundo); Serrano, J. (Josefina); Yébenes-Ramírez, M. (Manuel); Martínez-López, J. (Joaquín); Perez-Simon, J.A. (José Antonio); Amigo, M.L. (Mari Luz); Montesinos, P. (Pau); Martínez-Sánchez, P. (Pilar); García-Sanz, R. (Ramón); Florido-Ortega, Y. (Yanira); Sánchez-García, J. (Joaquín); Bergua, J. (Juan); Bernal, T. (Teresa); Ayala, R. (Rosa); Lavilla, E. (Esperanza); Tormo, M. (Mar); Costilla-Barriga, L. (Lisette); Llop, M. (Marta); Rapado, I. (Inmaculada); Janusz, K. (Kamila); Sanz, M.A. (Miguel A.); Herrera-Puente, P. (Pilar); Algarra, L. (Lorenzo); González-Díaz, M. (Marcos); Pérez-Santolalla, E. (Esther); Gomez-Casares, M.T. (María T.); Vazquez, I. (Iria); Barragán, E. (Eva); Noriega, V. (Víctor); Larrayoz, M.J. (María J.); Botella, C. (Carmen); Sargas, C. (Claudia); Soria, E. (Elena); Chillón, M.C. (María del Carmen); Calasanz-Abinzano, M.J. (Maria Jose); Martínez-Cuadron, D. (David); Alonso-Domínguez, J.M. (Juan M.); Marchante, I. (Inmaculada); Bilbao, C. (Cristina); Sayas, M.J. (María J.); Carrillo-Cruz, E. (Estrella)
    Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group.