Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement

Danika Di Giacomo,Paolo Fabio Fiumara,Valentina Pierini,Fabio Forghieri,Francesco Albano,Erika Borlenghi,Antonio Cuneo,Paolo Gorello,Mario Luppi,Marinella Veltroni,Martina Quintini,Caterina Matteucci,Monica Maccaferri,Giuseppe Rossi,Fabrizia Pellanera,Francesca Bettelli,Barbara Crescenzi,Roberta La Starza,Cristina Mecucci

doi:10.1007/s00277-021-04712-8

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.

Highlights

The Platelet-derived growth factor receptor B (PDGFRB) gene, at 5q32, encodes for the ß chain of the cell surface receptor for platelet-derived growth factor (PDGFRß), a class III receptor tyrosine kinase (RTK) that activates signaling pathways involved in cell growth and differentiation [1]
Eleven of fourteen patients were first observed in a non-aggressive phase (6 MPN/MDS, 2 CEL, 2 CMML, 1 aCML), 2 cases were first diagnosed as acute myeloid leukemia, and 1 case was diagnosed as myeloid sarcoma (Table 1)
We characterized a series of 14 cases with a myeloid neoplasm at diagnosis and a rearrangement of PDGFRB, providing data from in-depth genomic characterization by Single nucleotide polymorphism array (SNPa) and NGS analysis

Summary

Introduction

The PDGFRB gene, at 5q32, encodes for the ß chain of the cell surface receptor for platelet-derived growth factor (PDGFRß), a class III receptor tyrosine kinase (RTK) that activates signaling pathways involved in cell growth and differentiation [1]. PDGFRB is a frequent target of chromosomal translocations in a subgroup of hematological malignancies recognized in the 2017 World Health Organization (WHO) as a stand-alone category under “Myeloproliferative neoplasms with eosinophilia and gene rearrangement” [2. These disorders are presenting as chronic myeloid neoplasms, frequently as chronic myelomonocytic leukemia with eosinophilia [2], (hyper)-eosinophilia is not invariably present [3, 4]. PDGFRB is rearranged in lymphoid malignancies, including cases of both B- and T-cell acute lymphoblastic leukemia/lymphoma (ALL) [1, 4,5,6]. This treatment is successful, few series of cases with clinical and molecular monitoring have been reported [3, 4, 12]

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Results

Conclusion