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1.
Blood ; 137(3): 387-391, 2021 01 21.
Article in English | MEDLINE | ID: mdl-32814349

ABSTRACT

Interferon-α (IFN-α)-based treatments can induce hematologic and molecular responses (HRs and MRs, respectively) in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have been implicated in differential drug responses. We addressed the effect of common germline polymorphisms on HR and MR after treatment of PV in the PROUD-PV and CONTINUATION-PV studies in a total of 122 patients who received ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over a 36-month follow-up did not reveal any associations at the level of genome-wide statistical significance. Furthermore, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during treatment of myeloproliferative neoplasms. We did not observe any association of IFNL4 polymorphisms with HR in our study cohort; however, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair, including the protein-coding variants rs368234815/rs117648444) on MR (P = 3.91 × 10-4; odds ratio, 10.80; 95% confidence interval, 2.39-69.97) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of patients with PV based on IFNL4 functionality may allow for optimizing patient management during IFN-α-based therapy.


Subject(s)
Germ Cells/metabolism , Interferon-alpha/therapeutic use , Polycythemia Vera/drug therapy , Polycythemia Vera/genetics , Follow-Up Studies , Genetic Predisposition to Disease , Humans , Interleukins/genetics , Open Reading Frames/genetics , Polymorphism, Single Nucleotide/genetics , Treatment Outcome
2.
Blood ; 137(14): 1920-1931, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33202418

ABSTRACT

Somatic mutations of calreticulin (CALR) have been identified as a main disease driver of myeloproliferative neoplasms, suggesting that development of drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD) abolishes the ability of mutant CALR to oncogenically activate the thrombopoietin receptor (MPL). We therefore hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing a selective growth inhibitory effect on cells that depend on oncogenic CALR for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR-mutated cells than in CALR wild-type cells. Additionally, knockout or C-terminal truncation of CALR eliminated drug hypersensitivity in CALR-mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, disruption of the mutant CALR-MPL interaction, inhibition of the JAK2-STAT5 pathway, and reduction at the intracellular level of mutant CALR upon drug treatment. Our data indicate that small molecules targeting the GBD of CALR can selectively kill CALR-mutated cells by disrupting the CALR-MPL interaction and inhibiting oncogenic signaling.


Subject(s)
Calreticulin/metabolism , Hematoxylin/pharmacology , Protein Interaction Maps/drug effects , Receptors, Thrombopoietin/metabolism , Animals , Binding Sites/drug effects , Calreticulin/chemistry , Calreticulin/genetics , Cell Line , Drug Discovery , Humans , Mice , Molecular Docking Simulation , Mutagenesis, Site-Directed , Mutation , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Protein Binding/drug effects , Receptors, Thrombopoietin/chemistry
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