The 8p11 Myeloproliferative Syndrome: A Distinct Clinical Entity Caused by Constitutive Activation of <i>FGFR1</i>

Abstract

Several recurrent translocations that involve chromosome band 8p11 have been described in myeloid malignancies. These translocations target two distinct genes: (1) FGFR1, a receptor tyrosine kinase for fibroblast growth factors, and (2) MOZ, a putative histone acetyltransferase whose precise function remains to be defined. Disruption of FGFR1 is associated with a disease entity known as the 8p11 myeloproliferative syndrome (EMS)/stem cell leukemia-lymphoma syndrome, a chronic myeloproliferative disorder that frequently presents with eosinophilia and associated T-cell lymphoblastic lymphoma. The disease is aggressive and rapidly transforms to acute leukaemia, usually of myeloid phenotype. Currently, only allogeneic stem cell transplantation appears to be effective in eradicating or suppressing the malignant clone. To date, four gene fusions associated with distinct translocations have been described in EMS: the t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11q22) fuse ZNF198, CEP110, FOP and BCR, respectively, to FGFR1. The resulting fusion proteins have constitutive tyrosine kinase activity and activate multiple signal transduction pathways. These pathways and the fusion proteins are attractive targets for targeted signal transduction therapy.

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…Activating point mutations in KIT are found in some patients with systemic mast cell disease. Patients with 8p11 myeloproliferative syndrome have myeloproliferation frequently accompanied by non-Hodgkin lymphoma, in which both myeloid and lymphoma cells share fusions of the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) to multiple partners 97 . Finally, tyrosine kinases have been implicated in the pathogenesis of some acute leukaemias, principally in Ph + acute lymphoblastic leukaemia (ALL), in which BCR-ABL is found, and in acute myeloid leukaemia (AML), in which about a third of patients have activating mutations in the FLT3 (FMS-related tyrosine kinase 3) receptor tyrosine kinase.…”

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

“…30 Clonal eosinophilia in association with a T-NHL is generally very rare but regularly found in the 8p11 myeloproliferative syndrome or stem cell leukemia-lymphoma syndrome, which is associated with rearrangements of the FGFR1 gene on chromosome band 8p11. 5,31 The unique clinical phenotype of Eos-MPD in conjunction with T-cell lymphoma and progression to AML has now been reported in association with two distinct receptortyrosine kinases, FGFR1 and PDGFRA. Furthermore, the demonstration of FIP1L1-PDGFRA in both myeloid and T cells clearly indicates that this disease, like CML, is a stem cell disorder.…”

“…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.…”

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…”