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A Systematic, Evidence-Based Workflow for Classifying KMT2A Fusions in Acute Myeloid Leukemia.

Lauren M Petersen1, Rachana Sainger1, Paulina Sanchez1

  • 1Laboratory for Personalized Molecular Medicine, San Diego, California.

The Journal of Molecular Diagnostics : JMD
|July 24, 2025
PubMed
Summary
This summary is machine-generated.

A new workflow standardizes the classification of KMT2A fusions in acute myeloid leukemia (AML). This points-based system aids genetic diagnostic laboratories in accurately assessing oncogenicity for improved patient care.

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Area of Science:

  • Hematology
  • Molecular Oncology
  • Genetics

Background:

  • KMT2A fusions are key drivers in 5-10% of acute myeloid leukemia (AML) cases, linked to poor prognosis.
  • Accurate classification of these fusions is crucial for patient management, yet lacks established somatic guidelines.
  • The Laboratory for Personalized Molecular Medicine (LabPMM) developed a novel workflow to address this need.

Purpose of the Study:

  • To develop and validate a standardized workflow for classifying KMT2A fusions in AML.
  • To assess the oncogenicity of KMT2A fusions using a points-based evidence system.
  • To improve clarity and consistency in reporting KMT2A fusion findings.

Main Methods:

  • The LabPMM KMT2A Fusions Workflow was created, adapting a points-based system from existing somatic guidelines.
  • The workflow was tested on 100 previously identified KMT2A fusions from LabPMM's CAP/CLIA-certified gene panels.
  • Breakpoint locations in KMT2A and partner genes were analyzed to understand their role in leukemogenesis.

Main Results:

  • Of 100 KMT2A fusions reassessed, 97 had breakpoints in the major breakpoint cluster region.
  • Twenty distinct partner genes were identified, with MLLT3, ELL, AFDN, MLLT10, and AFF1 being the most common.
  • Five novel KMT2A partner genes (MYB, RC3H1, SNAPC3, STPG1, HPSE2) were identified, and 9 fusions had a classification change after reassessment.

Conclusions:

  • The LabPMM KMT2A Fusions Workflow provides a standardized, points-based approach for classifying KMT2A fusions in AML.
  • This workflow enhances clarity and consistency for genetic diagnostic laboratories.
  • It facilitates more accurate oncogenicity assessment, crucial for patient care in AML.