The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy

Abstract

EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), CML (chronic myeloid leukemia), CMML (chronic monomyelocytic leukemia), or mixed phenotype acute leukemia (MPAL). Most patients are resistant to traditional chemotherapy, and a minority of patients achieve long-term clinical remission after stem cell transplantation. Recently, the therapeutic effect of targeted tyrosine kinase inhibitors (such as pemigatinib and infigratinib) in 8p11 has been confirmed in vitro and clinical trials. The TKIs may become an 8p11 treatment option as an alternative to hematopoietic stem cell transplantation, which is worthy of further study.

Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan

“…All three cases with MLN- FGFR1 abnormalities in this report harbored t(8;13)(p11.2;q12), which is the most common chromosomal abnormality in MLN-FGFR1 abnormalities [ 1 ]. In this translocation, the partner gene with FGFR1 is ZNF198 (previously reported as ZMYM2 , FIM , and RAMP ) located at 13q11-12, and the zinc finger domain of ZNF198 is fused to the tyrosine kinase domain of FGFR1.…”

“…Recipient mice transplanted with bone marrow cells transfected with ZMYM2::FGFR1 developed myeloproliferation and intestinal T-cell lymphoma, and in immunodeficient mice, human cord blood CD34 + cells transfected with ZMYM2::FGFR1 showed expansion of multiple myeloid cell lineages and accumulation of blasts in BM [ 7 , 8 ]. In patients with t(8;13)(p11.2;q12), lymphadenopathy and hepatosplenomegaly are often the first symptoms, and most patients are diagnosed with T-LBL/T-lymphoma [ 1 ]. Consistent with this, all three patients in our study developed T-cell malignancies in their clinical course.…”

“…Chromosomal 8p11 abnormalities with Fibrocyte growth factor receptor 1 ( FGFR1) rearrangement is a rare hematopoietic disorder with widespread clinical and pathologic features, including myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), and MPN/MDS, often associated with eosinophilia, lymphadenopathy, usually T-lymphoblastic lymphoma/leukemia (T-LBL), and progression to acute myeloid leukemia (AML) [ 1 ]. The disease progresses rapidly, usually to acute leukemia within one year, and the prognosis is poor.…”

“…FGFR1 is a member of the receptor tyrosine kinase superfamily, and the molecular pathogenesis of MLN- FGFR1 abnormalities is characterized by the generation of fusion proteins with an intact kinase domain of FGFR1 [ 3 ]. Currently, it has been reported that 17 FGFR1 gene rearrangements exist in MLN- FGFR1 abnormalities, including 15 translocations, one insertion, and one inversion [ 1 ]. The difference of partner genes with FGFR1 rearrangement is thought to be the cause of the variety of phenotypes of MLN- FGFR1 abnormalities, which makes it difficult to list MLN- FGFR1 abnormalities as a differential diagnosis.…”

Case Report: A novel FGFR1 fusion in acute B-lymphoblastic leukemia identified by RNA sequencing

“…Liren Qian, Fifth Medical Center of the PLA General Hospital, China translocation involving FGFR1 gene. Seventeen FGFR1 fusions has been reported in EMS far, of which the most common are ZNF198-FGFR1, BCR-FGFR1 and CEP110-FGFR1 (3). Most EMS patients are diagnosed with CML (chronic myeloid leukemia), aCML (atypical chronic myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), or AML (acute myeloid leukemia).…”