Subclonal AGGF1::PDGFRB rearrangement in a myelodysplastic/myeloproliferative neoplasm with suboptimal response to imatinib

Myeloid/lymphoid neoplasms with PDGFRB rearrangements are rare hematologic malignancies with marked clinicopathologic and genetic heterogeneity. AGGF1 is an exceptionally rare PDGFRB fusion partner previously reported only in pediatric lymphoblastic leukemia. Here, we describe the first AGGF1::PDGFRB rearrangement in a myeloid neoplasm and characterize its clonal evolution.

A man older than 80 years of age with progressive leukocytosis, anemia, and thrombocytopenia underwent bone marrow examination, conventional karyotyping, next-generation DNA sequencing, and RNA sequencing.

The bone marrow showed features of a myelodysplastic/myeloproliferative neoplasm with neutrophilia. Molecular studies identified clonally dominant pathogenic DNMT3A, RUNX1, SF3B1, and WT1 mutations and KMT2A partial tandem duplication. RNA sequencing detected a subclonal AGGF1::PDGFRB fusion, supported by inv(5)(q13q33) in 6 of 20 metaphases. Hydroxyurea and imatinib produced a marked reduction in leukocyte count within 1 month. Two months later, however, the disease progressed to acute myeloid leukemia with acquisition of FLT3 internal tandem duplication, while AGGF1::PDGFRB was no longer detectable.

This case expands the spectrum of PDGFRB-rearranged myeloid neoplasms and demonstrates that a potentially targetable tyrosine kinase rearrangement may arise as a subclonal rather than a founding event. Defining clonal architecture and temporal evolution is therefore important for accurate disease classification, therapy selection, and interpretation of treatment response.