A global study for acute myeloid leukemia with RARG rearrangement

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Acute myeloid leukemia (AML) with retinoic acid receptor gamma (RARG) rearrangement mimics classic acute promyelocytic leukemia but is unresponsive to standard therapies.
• This AML subtype carries a poor prognosis, necessitating a deeper understanding of its characteristics and outcomes.

Purpose of the Study:

• To define the clinicopathological features, genomic landscape, and outcomes of AML with RARG rearrangements.
• To identify RARG rearrangement as a novel molecular subtype of AML.

Main Methods:

• Global cooperative study involving 29 institutions worldwide.
• Analysis of 34 patient samples for morphology, immunophenotyping, cytogenetics, and gene rearrangements.
• Genomic and transcriptomic profiling using RNA sequencing on 201 AML patients.

Main Results:

• RARG rearrangements were associated with bleeding (54.5%) and M3/M3v morphology (73.5%).
• Common immunophenotypic markers included CD33, CD13, MPO positivity and CD38, CD11b, CD34, HLA-DR negativity.
• None of the patients responded to ATRA/ATO; high 2-year mortality (66.5%) and relapse rates (68.7%) were observed.
• RNA sequencing identified RARG fusion samples clustering as a distinct molecular subtype (81.8%).

Conclusions:

• RARG rearrangement represents a novel and aggressive entity within AML.
• The poor prognosis and treatment resistance underscore the urgent need for targeted therapies for this AML subtype.