Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the aberrant proliferation of one or more myeloid lineages. As a preclinical research service provider dedicated to oncology preclinical development, Alfa Cytology offers comprehensive, customized one-stop preclinical research services for MPNs. Leveraging deep expertise in cancer biology, state-of-the-art in vivo modeling platforms, and integrated diagnostic and therapeutic development capabilities, our company provides end-to-end solutions spanning target validation, efficacy evaluation, pharmacokinetic and pharmacodynamic profiling, and biomarker discovery.
Characterized by the clonal proliferation of mature myeloid lineage cells within the bone marrow, Myeloproliferative Neoplasms (MPNs) comprise a heterogeneous group of chronic hematologic malignancies predominantly including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Driven by hematopoietic stem cell driver mutations that induce constitutive cytokine signaling, these diseases manifest through elevated peripheral blood counts, bone marrow hypercellularity, splenomegaly, an increased risk of thrombotic or hemorrhagic complications, and a propensity for leukemic transformation into acute myeloid leukemia (AML).
Fig.1 Association of mutational status with overall survival in MPNs. (Greenfield, G., et al., 2021)
At the molecular core of classical MPN pathogenesis lies the dysregulation of the JAK-STAT signaling pathway, most frequently triggered by somatic gain-of-function mutations in the JAK2 (notably JAK2 V617F), CALR (calreticulin), and MPL (thrombopoietin receptor) genes. These driver alterations induce ligand-independent activation of downstream cytokine receptor signaling cascades, promoting uncontrolled hematopoietic cell proliferation and survival while altering the bone marrow microenvironment through inflammatory cytokine hypersecretion, ultimately culminating in progressive marrow fibrosis and extramedullary hematopoiesis.
| Drugs | Targets | Mechanism of Action | Phase |
|---|---|---|---|
| Ruxolitinib | JAK1 / JAK2 | Selective ATP-competitive inhibitor suppressing downstream STAT phosphorylation and cytokine signaling. | Approved |
| Fedratinib | JAK2 / FLT3 | Selective JAK2 kinase inhibitor suppressing mutant signaling and FLT3-mediated proliferation. | Approved |
| Momelotinib | JAK1 / JAK2 / ACVR1 | Triple inhibitor blocking JAK signaling while downregulating hepcidin via ACVR1 to alleviate anemia. | Approved |
| Bomedemstat | LSD1 (KDM1A) | Lysine-specific demethylase 1 inhibitor modulating epigenetic stem cell self-renewal and lineage differentiation. | Phase II/III |
| Navitoclax | BCL-2 / BCL-xL | Dual BH3-mimetic inducing apoptosis in senescent and malignant hematopoietic stem cells. | Phase III |
Leveraging comprehensive oncology research capabilities spanning molecular biology, in vivo pharmacology, histopathology, and bioanalytical sciences, Alfa Cytology provides tailored preclinical services across the full spectrum of MPN research and drug development.
Assisting in compound screening, functional cell-based assays, kinase inhibitory profiling, downstream signal transduction analysis, and basic combination studies for candidate molecules.
Supporting biomarker evaluation, genetic mutation detection, allele burden analysis via digital PCR or sequencing technologies, and assay optimization for translational research.
Executing pharmacokinetics / pharmacodynamics evaluations, routine histopathological analysis of blood and bone marrow tissues, cytokine profiling, and initial efficacy and safety assessments.
Tailored to the precise genomic driver mutations and microenvironmental complexities of hematologic malignancies, specialized custom animal model development services are provided to establish predictive in vivo platforms for MPN research.
Engineered to faithfully mirror human MPN initiation, driver mutation dynamics, and multi-stage disease progression within an intact immune microenvironment, these custom-developed endogenous models allow for the long-term evaluation of targeted therapies and bone marrow fibrosis dynamics.
Cell Line‑Based In Vivo ModelsCustom-built through the precise engraftment of established human or mouse MPN cell lines into immunocompromised or syngeneic hosts, these models provide highly reproducible, fast-turnaround systems for rapid in vivo compound screening, target engagement validation, and systemic toxicity profiling.
Retroviral Transduction & Bone Marrow Transplantation (BMT) ModelsDeveloped via retroviral vector-mediated gene transfer into donor hematopoietic stem/progenitor cells followed by reconstitution in irradiated recipient mice, these customized transplantation models deliver rapid, highly penetrant phenotypic manifestations of severe myelofibrosis, marked splenomegaly, and extramedullary hematopoiesis.
To evaluate the pharmacodynamic profile of a candidate JAK inhibitor, Jak2-V617F knock-in mice were divided into treatment and vehicle control groups alongside age-matched wild-type controls. Animals received oral administration of either the test compound or vehicle over a multi-week dosing period, with baseline blood collected prior to initiation. Body weights and complete blood counts were routinely monitored at specified intervals throughout the study. Following treatment completion, animals were euthanized for harvest of spleens and bone marrow tissues to assess organ index and histological markers. Drug administration markedly attenuated elevated white blood cell counts in Jak2-V617F mice compared to vehicle-treated controls. Additionally, macroscopic examination revealed that targeted treatment effectively suppressed disease-associated splenomegaly, resulting in a significant decrease in spleen mass and index.
Fig.2 Pharmacodynamic evaluation of a targeted JAK inhibitor in the JAK2 V617F knock-in MPN mouse model. (A-C) Complete blood count parameters, including white blood cell (WBC), red blood cell (RBC), and platelet (PLT) counts across treatment groups. (D) Spleen index assessment following harvest at the study endpoint. Data are presented as mean ± SEM (n=6, ***p < 0.001, **p < 0.01).
Myeloproliferative neoplasms present substantial unmet needs for disease‑modifying therapies beyond symptom management. Alfa Cytology is uniquely positioned to accelerate MPN therapeutic development through integrated, customized preclinical research services that combine scientific excellence, operational efficiency, and regulatory expertise. From genetically engineered mouse models to patient-derived systems, from target validation to IND-enabling studies, our company delivers the comprehensive support required to advance novel MPN therapeutics from concept to clinic. For more information about our MPN preclinical research capabilities or to discuss a specific project, please contact our scientific team.
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