# Generation of novel murine B-cell lymphoma models using mosaic analysis by dual recombinase-mediated cassette exchange (MADR) to more closely resemble human B-cell lymphomas

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $118,869

## Abstract

PROJECT SUMMARY
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL). DLBCL
tumors are highly heterogeneous and molecular profiling has revealed 100s of mutations that can be clustered
into five distinct prognostically relevant sub-groups, however biomarkers that include TME elements have not
been developed. In our parent R01, we hypothesized that successful development of next generation
immune targeting therapies for lymphoma will require spatially resolved, highly multiplexed single cell
based biomarkers of TME composition and structure. For that project we proposed to perform imaging
mass cytometry analysis (IMC) on over 2000 cases of aggressive B cell lymphoma with the following aims:
Specific Aim 1: Validate spatially-derived protein biomarkers of DLBCL outcomes (n=830 patients). Specific
Aim 2: Analyze the single cell topology of histologically diverse aggressive B cell lymphomas (n=1380) to
identify shared TME based biomarkers across all aggressive B cell lymphoma. Specific Aim 3: Determine
which TME elements modulate chemoresistance and mediate response to immune therapies in lymphoma
through in vitro and in vitro model systems. A significant limitation of Aim 3 was that it relied on a single
syngeneic model system, A20, that does not represent that genetic diversity or complexity seen in DLBCL.
This was due to a major gap in the field as model systems that represent the five genetic sub-groups have not
been developed. In this revision, we propose a new Aim, Revision Aim 4, where we will apply the IMAT
supported technology Mosaic Analysis by Dual Recombinase-mediated cassette exchange (MADR) to rapidly
develop complex genetic models of DLBCL that recapitulate the genetic diversity seen in human disease. This
will allow us to perform functional validation of the spatial biomarkers we identify in Aims 1 and 2 of the parent
grant in the context of each specific mutational subtype. This will significantly enhance the impact of the
original grant and be the first application of MADR technology in a hematologic cancer. Once established these
MADR derived mouse models will enable testing of targeted therapies in each genetic sub-group, which is
currently not possible with the currently available pre-clinical models.

## Key facts

- **NIH application ID:** 10799433
- **Project number:** 3R01CA266544-02S1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Akil Merchant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $118,869
- **Award type:** 3
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799433

## Citation

> US National Institutes of Health, RePORTER application 10799433, Generation of novel murine B-cell lymphoma models using mosaic analysis by dual recombinase-mediated cassette exchange (MADR) to more closely resemble human B-cell lymphomas (3R01CA266544-02S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10799433. Licensed CC0.

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