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

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.