Biallelic TET2 mutation sensitizes to 5'-azacitidine in acute myeloid leukemia.

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Stölzel F
  • Fordham, Sarah E.
  • Nandana, Devi
  • Lin, Wei-Yu
  • Blair, Helen
  • Elstob, Claire
  • Bell, Hayden L.
  • Mohr, Brigitte
  • Ruhnke, Leo
  • Kunadt, Desiree
  • Dill, Claudia
  • Allsop, Daniel
  • Piddock, Rachel
  • Soura, Emmanouela-Niki
  • Park, Catherine
  • Fadly, Mohd
  • Rahman, Thahira
  • Alharbi, Abrar
  • Wobus, Manja
  • Altmann, Heidi
  • Röllig C
  • Wagenführ L
  • Jones, Gail L.
  • Menne, Tobias
  • Jackson, Graham H.
  • Marr, Helen J.
  • Fitzgibbon, Jude
  • Onel, Kenan
  • Meggendorfer, Manja
  • Robinson, Amber
  • Bziuk, Zuzanna
  • Bowes, Emily
  • Heidenreich, Olaf
  • Haferlach, Torsten
  • Villar, Sara
  • Ariceta, Benat
  • Ayala Diaz R
  • Altschuler, Steven J.
  • Wu, Lani F.
  • Prosper, Felipe
  • Martinez-Lopez, Joaquin
  • Bornhäuser M
  • Allan, James M.

Grupos

Abstract

Precision medicine can significantly improve outcomes for cancer patients, 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 (Ara-C), 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 to cells with monoallelic mutation. 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 cancer patients.

Datos de la publicación

ISSN/ISSNe:
2379-3708, 2379-3708

JCI Insight  AMER SOC CLINICAL INVESTIGATION INC

Tipo:
Article
Páginas:
-
PubMed:
36480300
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
3,640 SCImago
Cuartil:
Q1 SCImago

Citas Recibidas en Web of Science: 8

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Keywords

  • Cancer; Hematology; Leukemias; Molecular genetics

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