436
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→Cancer Category/Type
precursor-B lymphoblastic leukaemia/
precursor-B lymphoblastic leukaemia/
lymphoma or AML. (.70).
lymphoma or AML. (.70).
8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a rare disorder molecularly associated with fusion genes between the tyrosine kinase receptor gene FGFR1, located in 8p11, and several partner genes, including ZMYM2 (wang et al).
Previous studies have shown that EMS is usually resistant to conventional chemotherapies with a poor median survival rate of less than 12 months.1 Although FGFR1-involved fusion proteins are potential therapeutic targets, no satisfactory results have been achieved using tyrosine kinase inhibitors (TKIs) including imatinib3,4 and dasatinib.5 (wang et al).
In EMS, multiple genes, including ZMYM2, FGFR1OP, BCR, NUP98, FGFR1OP2, TRIM24, MYO18A, CPSF6, LRRFIP1, CNTRL, ERVK-61 and the recently identified SQSTM1,6 were detected as fusion partners with FGFR1 with a breakpoint in the 8p11–12 locus. Among these fusion genes, ZMYM2-FGFR1 is the most common type. The ZMYM2 proline-rich region, which mediates protein oligomerization, and the FGFR1 tyrosine kinase domain are conserved in the fusion protein. The abnormal oligomerization of ZMYM2-FGFR1 leads to constitutive activation of its tyrosine kinase.7 (wang et al).
FGFR1 fusion genes are associated with a disease entity initially referred to as the 8p11 myeloproliferative syndrome or stem cell leukemia/lymphoma.9,53 Fourteen different fusion genes have now been described. The 3 most common reciprocal translocations include t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), resulting in fusions of ZMYM2, CNTRL, and FGFR1OP, respectively, to FGFR1.54⇓-56 The transforming activity of the various FGFR1 fusion proteins has been demonstrated by conversion of the IL-3-dependent Ba/F3 cell line to growth factor independence and induction of a myeloproliferative neoplasm in murine models.57,58 (Reiter and Gotleib)
The clinical/laboratory characteristics typically reflect features of chronic myeloid neoplasms and variable eosinophilia.9 Patients may also present as de novo AML without an antecedent MPN. There is a high incidence of T-lymphoblastic lymphomas, particularly in association with a t(8;13) and a ZMYM2-FGFR1 fusion gene,9,53,54 which may occur at diagnosis or during the course of disease, reflecting a myeloid/lymphoid stem cell origin. The clinical course is aggressive as a result of rapid progression to blast phase/secondary acute leukemia, usually of myeloid phenotype, less commonly B-ALL, within 1 or 2 years of diagnosis. The variability in the clinical presentation may be a result of specific moieties of the partner genes and signaling via different intracellular pathways.59 The t(8;22) is often associated with a clinical and hematologic picture very similar to that seen in BCR-ABL1-positive CML with basophilia,58,60 whereas thrombocytopenia and monocytosis resembling CMML are more frequently present in t(6;8)56 and t(8;9).55,61 The t(6;8) may also present with a PV-like disease,62 and eosinophilia may be absent in t(6;8) and t(8;22).(Reiter and Gotleib)
==Gene Overview==
==Gene Overview==