Genetically Engineered Models
Chronic myelomonocytic leukemia (CMML) animal models serve as a vital bridge between basic research and clinical application by faithfully mimicking the disease's driver mutations and hematological phenotypes. To overcome the challenges in CMML animal model development, Protheragen leverages advanced technological platforms to create highly precise models that accelerate the candidate drug development pipeline from discovery to market approval.
Animal models for chronic myelomonocytic leukemia (CMML) are essential pre-clinical tools designed to recapitulate the dual pathological features of this myelodysplastic/myeloproliferative neoplasm. These models are primarily engineered through the introduction of recurrent human CMML-associated mutations—such as those in TET2, SRSF2, ASXL1, and RAS—into the murine hematopoietic system. By mimicking the genetic landscape, these models successfully reproduce key disease hallmarks, including persistent monocytosis, dysplastic hematopoiesis, and a variable propensity for transformation to acute myeloid leukemia (AML). This fidelity makes them indispensable systems for elucidating disease-initiating mechanisms, studying the complex cooperativity between mutations, and evaluating the efficacy of novel therapeutic agents.
Fig.1 Summary of commonly used mouse model methods to study acute myeloid leukemia (AML). (Kurtz K J, et al., 2022)
As a leading provider of preclinical research services, Protheragen offers specialized and precise animal model development services for chronic myelomonocytic leukemia (CMML) research. Our team utilizes advanced molding techniques, including gene editing and bone marrow transplantation, to create models that accurately recapitulate recurrent driver mutations and the complex hematopathological phenotypes of CMML.
Genetically Engineered Models
Protheragen specializes in developing a comprehensive suite of genetically engineered CMML models, utilizing targeted gene knockout and knock-in technologies to faithfully recapitulate the complex genetic landscape of the human disease.
Patient-Derived Xenograft (PDX) Models
Patient-derived xenograft (PDX) models are a powerful preclinical platform generated by transplanting primary human CMML cells into immunodeficient mice, thereby preserving the genetic complexity, cellular heterogeneity, and therapy response of the original patient's disease. The transplanted patient cells critical for establishing these models primarily include:
| Model Name | Ptpn11-Flox Mice |
|---|---|
| Model Type | Genetically Engineered Mouse Models (GEMMs) |
| Modeling Method | Conditional Knockout |
| Sales Status | Sperm Cryopreservation |
| Detailed Description | These strains carry loxP sites flanking Exon 4 of Ptpn11 gene. When crossed with a Cre recombinase-expressing strain, this strain is useful in eliminating tissue-specific conditional expression of Ptpn11 gene. |
| Applications | The Ptpn11-Flox mouse model is primarily applied for validating SHP2 as a therapeutic target, investigating the role of hyperactive RAS-MAPK signaling in CMML pathogenesis, and conducting preclinical efficacy studies for novel SHP2 inhibitors. |
To investigate the role of epigenetic regulators in leukemogenesis, this study established a constitutive Arid4a knockout mouse model using gene editing technology. The role of Arid4a in the multi-step progression from pre-malignancy to overt leukemia was previously unclear. Disruption of Arid4a leads to a myelodysplastic/myeloproliferative neoplasm in mice that closely mimics human chronic myelomonocytic leukemia (CMML), with progression to acute myeloid leukemia (AML).
The Arid4a-/- mice recapitulated a step-wise progression from pre-leukemia to a frank myeloproliferative disorder:
Fig.2 Serial hematological profiling of Arid4a⁻/⁻ mice reveals a progression from pre-leukemic ineffective hematopoiesis to overt CMML. Complete blood count (CBC) analysis of wild-type (WT) and Arid4a⁻/⁻ mice across two age cohorts: 2-5 months (WT, n=35; Arid4a⁻/⁻, n=30) and >5 months (WT, n=25; Arid4a⁻/⁻, n=25). Data are presented as mean with 95% confidence intervals. P-values were calculated by Student's t-test. *p < 0.05, ***p < 0.001 vs. age-matched WT.This case study validates the Arid4a-/- mouse as a highly relevant and dynamic model for studying leukemogenesis. The model faithfully recapitulates the human disease continuum, progressing from initial ineffective hematopoiesis (a pre-leukemic state) to a CMML-like myeloproliferative disorder, and ultimately to AML. This makes it a powerful preclinical tool for elucidating the role of epigenetic dysregulation in leukemia and for evaluating novel therapeutic strategies for both pre-leukemic and leukemic conditions.
Leveraging precise animal models, Protheragen is dedicated to providing a comprehensive suite of preclinical research services for chronic myelomonocytic leukemia (CMML). Our integrated services include in-depth pharmacodynamics (PD), pharmacokinetics (PK), and toxicology studies, all designed to de-risk and accelerate the development of novel targeted therapies and support their regulatory approval. If you are interested in our animal model development services, please do not hesitate to contact us for more details and quotation information.
Reference
Protheragen's preclinical research services evaluate the pharmacodynamics, pharmacokinetics, and safety of drug candidates for rare blood disorders.
Myeloproliferative Disorders (MPDs)
Bone Marrow Failure Syndromes (BMFS)