Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement

Abstract

Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100-200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.

Keywords: Chromosome translocations; Imatinib; KAZN; Molecular monitoring; PDGFRB.

Fig. 1

Cytogenetic and molecular characterization of the novel KAZN::PDGFRB fusion. a FISH break-apart assay with fosmids WI2-0883F15 (spectrum green) and WI2-0968K05 (spectrum orange) for KAZN/1p36.21 showed a fusion signal on normal chromosome 1, a red signal on der(1), and a green signal on der(5) in case no. 14 (Table 1). b Direct sequencing showed an in-frame fusion joining exon 4 of KAZN to exon 12 of PDGFRB. GenBank accession numbers: NM_201628.3 for KAZN and NM_002609.3 for PDGFRB. nl, normal; ex, exon

Fig. 2

The mutational background of PDGFRB-positive cases. Oncoprint heatmap showing mutations found at diagnosis in cases with a rearrangement of PDGFRB. Somatic mutations are reported in red and germline mutations in green; gray, non-mutated genes