Myeloproliferative Disorders with Translocations of Chromosome 5q31–35: Role of the Platelet-Derived Growth Factor Receptor Beta

Abstract

Acquired reciprocal chromosomal translocations that involve chromosome bands 5q31–33 are associated with a significant minority of patients with BCR-ABL-negative chronic myeloid leukemias. The most common abnormality is the t(5;12)(q33;p13), which fuses the ETV6/TEL gene to the platelet-derived growth factor receptor-β (PDGFRB), a receptor tyrosine kinase that maps to 5q33. PDGFRB is disrupted by other translocations and to date four additional partner genes (H4, HIP1, CEV14 and Rab5) have been reported. Clinically, most patients present with a myeloproliferative disorder (MPD) with eosinophilia, eosinophilic leukemia or chronic myelomonocytic leukemia and thus fall into the broader category of myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS). With the advent of targeted signal transduction therapy, patients with rearrangement of PDGFRB might be better classified as a distinct subgroup of MPD/MDS.

Tyrosine kinase fusion genes in chronic myeloproliferative diseases

“…8,9 The clinical phenotype of EMS, and also that associated with 5q rearrangements, has been reviewed in detail elsewhere. 10,11 Briefly, patients with a 5q31-33 rearrangement present at a median age of between 50 and 60 years and, remarkably, virtually all patients are male. Patients with EMS present at a…”

“…16 Thrombocytosis and monocytosis have been described relatively frequently in patients with a t(8;9), and thus the disease with this translocation resembles CMML but without major dysplastic signs in either lineage. 11,22 The incidence of T-NHL appears to be considerably higher in cases that present with a t(8;13) compared to patients with variant translocations. For example, in a recent survey 13/16 patients with a t(8;13) had T-NHL compared to 3/11 patients with a t(6;8) or t(8;9).…”

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma

“…Notably, two clear break point clusters have been identified at chromosome bands 5q31-33 and 8p11 that target the platelet-derived growth factor receptor B (PDGFRB) and the fibroblast growth factor receptor 1 (FGFR1) genes, respectively. 1,5,6 More recently, a cytogenetically cryptic deletion that targets PDGFRA was identified in patients with Eos-MPD leading to a FIP1L1-PDGFRA fusion gene. [7][8][9] All these rearrangements generate constitutively active tyrosine kinase fusion proteins which are structurally and functionally analogous to BCR-ABL in chronic myeloid leukemia (CML) and therefore ideal targets for signal transduction therapy.…”

A novel ETV6-PDGFRB fusion transcript missed by standard screening in a patient with an imatinib responsive chronic myeloproliferative disease

“…Treatment of severe autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab We read with interest the article by Karlsson et al 1 in Leukemia (2007), which reports five patients treated successfully with alemtuzumab (anti-CD52) for refractory autoimmune hemolytic anemia (AIHA) complicating B-cell chronic lymphocytic leukemia (B-CLL). AIHA occurs in about 5% of patients with B-CLL and requires treatment including corticosteroids, cytotoxic drugs, splenectomy or immunosuppressive drugs.…”

“…More recently, however, imatinib has emerged as the standard therapy for PDGFR-rearranged patients, with most experiencing sustained haematologic and cytogenetic remission, and many achieving molecular remission. 1 Molecular confirmation of a PDGFR rearrangement is therefore important for appropriate clinical management and monitoring response to therapy. For the t(5;12)(q31-33;p13), confirmation of the presence of ETV6-PDGFRB is particularly important since many cases with this translocation have a distinct molecular aetiology, with upregulation of IL-3 expression and no involvement of PDGFRB.…”