Epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.

Journal: Nature communications
Published Date: Jul 29, 2025

Abstract

Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation on patient samples confirms high concordance between epigenomic signatures and genomic lesions, though uniquely rare karyotypes remained challenging due to limited available training data. These results unveil the potential for increased affordability, speed, and accuracy for patients in need of complex molecular diagnosis and prognosis.

Authors

  • Francisco Marchi
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Vivek M Shastri
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Richard J Marrero
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Nam H K Nguyen
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Antonella Öttl
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Ann-Kathrin Schade
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Marieke Landwehr
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Olga Krali
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • Jessica Nordlund
    Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Matin Ghavami
    Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA.
  • Fernando Sckaff
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • Vikash K Mansinghka
    Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
  • Xueyuan Cao
    Department of Health Promotion and Disease Prevention, University of Tennessee Health Science Center, Memphis, TN, USA.
  • William Slayton
    Department of Pediatrics Hematology, University of Florida, Gainesville, FL, USA.
  • Petr Starostik
    University of Florida Health Cancer Center, Gainesville, FL, USA.
  • Christopher R Cogle
    University of Florida Health Cancer Center, Gainesville, FL, USA.
  • Raul C Ribeiro
    Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Jeffrey E Rubnitz
    Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Jeffery Klco
    Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Abdelrahman Elsayed
    Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Alan S Gamis
    Hematology/Oncology/BMT, Children's Mercy Kansas City, Kansas City, MO, USA.
  • Timothy J Triche
    Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
  • Rhonda Ries
    Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • E Anders Kolb
    Leukemia & Lymphoma Society, Washington D.C., USA.
  • Richard Aplenc
    Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Todd Alonzo
    University of Southern California Keck School of Med, Los Angeles, CA, USA.
  • Stanley Pounds
    Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Soheil Meshinchi
    Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Jatinder K Lamba
    Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA. jatinderklamba@ufl.edu.

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