Deactylase inhibition in myeloproliferative neopla

Authors: Sridurga Mithraprabhu George Grigoriadis Tiffany Khong Andrew Spencer

Publish Date: 2010/12/03

Volume: 28, Issue: 1, Pages: 50-57

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Abstract

Myeloproliferative neoplasms MPN are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages myeloid erythroid and/or megakaryocytic The MPNs include eight haematological disorders chronic myelogenous leukemia CML polycythemia vera PV essential thrombocythemia ET primary myelofibrosis PMF systemic mastocytosis SM chronic eosinophilic leukemia not otherwise specified CEL NOS chronic neutrophilic leukemia CNL and unclassifiable MPN MPN U Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors TKIs for BCRABL1+ CML and JAK2 inhibitors for PV ET and PMF Histone deacetylase inhibitors HDACi are a novel class of drugs capable of altering the acetylation status of both histone and nonhistone proteins thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation differentiation immune responses angiogenesis and survival Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the proapoptotic effects on MPN cells This review provides a review of preclinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNsThe World Health Organization WHO classification of haemopoietic and lymphoid neoplasms was revised in 2008 1 This represented a major improvement over the 2001 WHO classification system whereby myeloid neoplasms are now classified into five categories acute myeloid leukemia AML myelodysplastic syndromes MDS myeloproliferative neoplasms MPN MDS/MPN and myeloid and/or lymphoid malignancies associated with eosinophilia and plateletderived growth factor receptor PDGFR or fibroblast growth factor receptor 1 FGFR1 rearrangements MPN are subclassified into eight separate entities chronic myelogenous leukemia CML polycythemia vera PV essential thrombocythemia ET primary myelofibrosis PMF systemic mastocytosis SM chronic eosinophilic leukemia not otherwise specified CEL NOS chronic neutrophilic leukemia CNL and unclassifiable MPN MPNUThe MPN are clonal haemopoietic stem cell disorders characterized by proliferation of one or more haemopoietic lineages Occurrence is primarily in the 5th to 7th decade of life however CML and ET have been described in children The incidence of MPN as a group is 610/100000 population annually 2 Collectively MPN are characterised by a hypercellular bone marrow with effective haemopoiesis Over time splenomegaly and hepatomegaly occur as a result of sequestration of blood cells and extramedullary proliferation of haemopoietic cells Despite an initially indolent course MPN progress over time and have the potential to transform to acute leukaemia This manifests clinically as progressive organomegaly worsening of peripheral cytopenias and an increasing numbers of circulating blast cellsThe diagnosis of CML requires the presence of BCRABL1 while its absence is required for all other MPN CML remains the prototype for the identification and classification of myeloid neoplasms The enhanced tyrosine kinase activity of BCRABL1 results in constitutive activation of a number of signal transduction pathways resulting in the leukemic phenotype observed in CML BCRABL1 provided the first bona fide therapeutic target for tyrosine kinase inhibitors TKIs This has revolutionized the management of CML a disorder previously fatal without allogeneic stem cell transplantationPV ET and PMF make up the nonleukemic MPN Clonal proliferation is responsible for the overlapping expansion of erythropoietic granulopoietic and megakaryocytic components in the marrow and in advanced disease the liver and spleen A single acquired point mutation V617F of the cytoplasmic Janusassociated tyrosine kinase JAK2 occurs heterozygous or homozygous in the marrow and blood of almost all patients with PV and in approximately 50 of patients with ET and PMF and is responsible for the uncontrolled myeloproliferation associated with these disorders JAK2 is involved in transducing signals from cytokines and growth factors including erythropoietin EPO granulocytemacrophage colonystimulating factor GMCSF and thrombopoietin TPO The mutation occurs in a highly conserved region of the pseudokinase domain that is believed to negatively regulate JAK2 signaling In PV the presence of JAK2 homozygosity increases with time Additional MPNassociated molecular markers include mutations of MPL TET2 and KIT but the diagnostic utility of MPL and TET2 mutations is limited by a low mutational frequencyIn SM presence of the D816V KIT mutation is expected but not essential for diagnosis CEL NOS should be distinguished from both PDGFRrearranged or FGFR1rearranged neoplasms and hypereosinophilic syndrome HES CNL is a rare myeloproliferative disease with only 150 cases reported 1 and is characterized by sustained neutrophilia bone marrow hypercellularity and hepatosplenomegaly The BCRABL1 fusion gene is undetectable in CNL and further discrimination is required to distinguish CNL from other MPNsPrior to any effective therapy the median survival for CML was 2–3 years 3 Subsequently intereferonγ IFNγbased approaches resulted in 10 year overall survival OS rates of approximately 25 4 The 10year OS for allogeneic haemopoietic stem cell transplantation HSCT varied widely from 10 to 70 depending on patient age phase of disease and donor type 5 6 In the current era of tyrosine kinase inhibitor TKI therapy 5year OS with imatinib is 80–95 5 7 however acquired resistance to imatinib in patients leads to a clinical impasse In addition to BCRABL1 gene amplification resulting in overexpression of BCRABL1 protein or point mutations that prevent the binding of the inhibitor to the kinase domain 8 9 several groups have demonstrated other forms of BCRABL1independent imatinib resistance 10 11 12 Interestingly BCRABL1independent imatinibresistant K652 cells display aberrant protein acetylation and increased sensitivity to histone deactylase inhibitors HDACi 12PV and ET are relatively indolent disorders that result in a modest reduction of survival particularly evident after the first decade from diagnosis In contrast PMF has a more aggressive clinical course with a median survival of approximately 5 years although younger patients with lowrisk disease may experience survival in excess of 10 years 13 With the possible exception of IFNγ use in PV 14 15 16 therapy for classical MPN is aimed at ameliorating the signs and symptoms of myeloproliferation including anaemia and/or thrombocytopenia and to reduce the risk of thrombosis Patients with PMF and postET/PV MF have progressive cytopenias extramedullary haemopoiesis manifesting as splenomegaly and/or hepatomegaly significant constitutional symptoms the potential for blastic transformation and subsequently premature death 17 18 A number of novel therapeutic strategies have been explored in these patients including farnesyltransferase inhibition 19 proteosome inhibition 20 and immunomodulation with lenalidomide 21 but with limited efficacy Since current therapies rarely offer more than a palliative benefit the urgent need for improved therapeutic options for PMF and postET/PV MF has resulted in therapeutic targeting of the JAK2V617F mutation a common molecular link that unifies the pathogenesis of these MPNs A selective JAK1/2 inhibitor INCB018424 demonstrated prolonged survival in a preclinical murine model of JAKV617F + MPN 22 and preliminary results from a phase 1/2 study resulted in objective and subjective improvements in patients with PMF and postET/PV MF 22 These targeted therapeutic approaches are promising however other novel agents need to be explored

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