# Defining the epigenetic landscape and therapeutic vulnerabilities of Richter's syndrome in CRISPR-based mouse models

> **NIH NIH K22** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $196,020

## Abstract

Project Summary/Abstract
Richter’s syndrome (RS) is a critical complication of up to 10% of chronic lymphocytic leukemia (CLL) patients,
which develops as an aggressive transformation into a diffuse large B cell histology, and is mostly refractory to
existing therapies. RS pathogenesis remains largely unknown and cellular and mouse models for molecular
studies are limited. To address this challenge, Dr. ten Hacken has developed novel human-genetics inspired
mouse models through CRISPR-Cas9 multiplexed B-cell editing, recapitulating CLL transformation into RS.
Already through her preliminary studies, Dr. ten Hacken demonstrated how selected mutational co-occurrences
facilitate disease transformation, and are associated to distinct transcriptional changes and therapeutic
vulnerabilities—work that is presently near completion. Dr. ten Hacken is now planning to introduce a new set of
mutations in genes involved in epigenetic programming of B cells, which were identified as putative RS drivers
in recent human genomic analyses. In Aim 1, Dr. ten Hacken will introduce epigenetic drivers in mice to assess
the impact of the selected alterations (and their combinations) on CLL transformation. As part of this Aim, Dr.
ten Hacken will also assess the transcriptional and genetic faithfulness of these models to human disease. In
Aim 2, Dr. ten Hacken will functionally characterize the modeled gene mutations, while dissecting changes in
the epigenetic landscape underlying transformation of CLL into RS. Epigenetic dependencies identified through
these studies will be cross-compared with human RS datasets and validated in human primary samples with
similar genetic make-ups. In Aim 3, Dr. ten Hacken will perform in vitro and in vivo preclinical testing of a panel
of agents (comprehensive of chemotherapy and novel targeted agents) in order to design mutation (or co-
mutation) specific treatment strategies. To carry out the proposed work, Dr. ten Hacken has enlisted
collaborators who are experts in computational biology, systems immunology, mouse pathology, molecular
pharmacology, biostatistics, functional genomics and epigenetics. Dr. ten Hacken has outlined a 3-year career
development plan that will allow her to foster her personal professional development (including leadership, grant
writing, negotiation and communication skills), and to gain additional scientific training in bioinformatics and
biostatistics. Dr. ten Hacken’s independent research program will be focused on translational research in
hematological malignancies, with the longer-term objective of undertaking clinical correlative research and
functional genomic analyses of other lymphoid and myeloid malignancies. Through her proposed work, Dr. ten
Hacken anticipates to contribute 2 high-impact manuscripts within the award term. She will present yearly at
international conferences, and will be ready for her first R01 submission towards the end of Year 2. The proposed
studies are expected to provide cri...

## Key facts

- **NIH application ID:** 10844347
- **Project number:** 5K22CA269556-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Elisa ten Hacken
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $196,020
- **Award type:** 5
- **Project period:** 2023-05-19 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844347

## Citation

> US National Institutes of Health, RePORTER application 10844347, Defining the epigenetic landscape and therapeutic vulnerabilities of Richter's syndrome in CRISPR-based mouse models (5K22CA269556-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10844347. Licensed CC0.

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