AML Humouse: A humanized mouse model of AML with an autologous human immune system

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Humouse: A humanized mouse model of AML with an autologous human immune system
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Inventors
Professor Jianzhu Chen
Koch Institute for Integrated Cancer Research, MIT
External Link (ki.mit.edu)
Adam Drake
Koch Institute for Integrated Cancer Research, MIT
Mandeep Kaur
Koch Institute for Integrated Cancer Research, MIT
External Link (chen-lab.mit.edu)
Ryan Phennicie
Koch Institute for Integrated Cancer Research, MIT
Managed By
Michelle Hunt
MIT Technology Licensing Officer
Patent Protection

A humanized mouse model of de novo human acute myeloid leukemia with a matching human immune system

Provisional Patent Application Filed

Applications

The "AML humouse" is a humanized mouse model of de novo Acute Myeloid Leukemia (AML).  It hosts an autologous human immune system, meaning that it is a genetic match to the engrafted human leukemic cells. The model is uniquely suited for the development and pre-clinical testing of novel AML therapies, particularly those that require human immune system interaction. Specifically, AML humice can be used to assess the toxicity of new treatments prior to clinical testing, understand the mechanisms underlying cancer development in an in vivo context, discover new drug targets in AML, and develop new immunotherapies.

Problem Addressed

Existing animal models of AML include xenograft models of transplanted patient leukemic cells, chemically and virally induced leukemic models, and genetically engineered mouse models in which a human oncogene is introduced into the native mouse locus. These methods produce variable disease onset, have poor/no penetrance, or are better suited to model a leukemia that is not AML (e.g., B cell leukemia). Additionally, none of these models are suitable for testing treatments that require interaction with a human immune system. The AML humouse is unique in that it hosts two populations of human cells: one that develops AML and one that generates a normal human immune system. This expands their utility with respect to disease modeling and drug testing. Additionally, humice exhibit 100% disease penetrance and a shorter latency to disease onset compared to existing models. 

Technology

The humouse is generated by engrafting human hematopoietic stem cells (HSCs) into immunocompromised mice. A portion of the transplanted HSCs express a lentiviral vector encoding a mutated version of nucleophosmin (NPM1), an oncogene deregulated in ~30% of adult AML cases in the U.S. The transduced HSCs develop AML, whereas the un-transduced HSCs differentiate into a normal human immune system. These two groups of cells are a genetic match and coexist in the same recipient mouse, allowing for the study of their interaction in various contexts (e.g., early cancer development; drug treatment). The leukemic mice exhibit disease characteristics that mirror AML patient symptoms (e.g., dramatic weight loss, anemia, expanded myeloid population in the blood and bone marrow, and leukemic blast cells in the blood). The model can be used as a pre-clinical platform for drug testing and to better understand the role of the human immune system in cancer development. 

Advantages

  • Clinically relevant model-- disease characteristics mirror AML patient symptoms 
  • Can be used to study the development of human leukemia in vivo 
  • Can be used to study the role of the human immune system in leukemia development and progression 
  • Ideal for in vivo drug toxicity assays that require a human cell response