Acute myeloid leukemia with 4q12 rearrangements involving CHIC2: "pitfalls" in fluorescence in situ hybridization diagnosis of PDGFRA rearrangements.

Chromosome 4q12 rearrangements are recurrent in hematologic malignancies, most frequently involving PDGFRA. Fluorescence in situ hybridization (FISH) is routinely used for detecting 4q12 rearrangements. This study aimed to clarify 4q12 rearrangements misdiagnosed by FISH and explore the transcriptomic profile of acute myeloid leukemia (AML) with CHIC2 rearrangements. Fluorescence in situ hybridization with a PDGFRA/CHIC2/FIP1L1 probe set detected 4q12 rearrangements. RNA sequencing (RNA-seq) characterized fusion transcripts and compared transcriptomic profiles between CHIC2-rearranged AML and NPM1-mutated controls, identifying differentially expressed genes and enriched pathways. Previously reported PDGFRA-independent 4q12 cases were reviewed. RNA sequencing of 2 AML cases with FISH signals suggestive of PDGFRA rearrangement identified CHIC2 fusions instead: a novel CDK6::CHIC2 and a known ETV6::CHIC2. Integrating our cases with a systematic literature review, we identified 41 hematologic neoplasms with PDGFRA-independent 4q12 rearrangements, of which 38 (92.7%) were AML. The 4q12 breakpoints most frequently involved CHIC2 (27 cases, 65.9%), followed by GSX2, SCFD2, and intergenic regions. Among 15 cases assessed by both FISH and molecular methods, FISH misclassified 9 (60.0%; 9/15) as PDGFRA rearranged; subsequent molecular testing revealed rearrangements of genes adjacent to PDGFRA (eg, CHIC2, GSX2) or intergenic regions. Transcriptomic profiling of CHIC2-rearranged AML revealed a distinct expression signature with 492 differentially expressed genes, including PDGFRA upregulation. Pathway analysis showed significant enrichment for cytokine-cytokine receptor interaction and JAK-STAT signaling (false discovery rate <0.05). Molecular methods such as RNA-seq are effective for resolving cryptic 4q12 rearrangements in cases where FISH falsely suggests PDGFRA involvement. The distinct transcriptional profile of CHIC2-rearranged AML suggests dysregulated cytokine signaling and JAK-STAT activity in its pathogenesis.