# Comprehensive dissection of the CLL genome and phenome to improve patient outcomes

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $1,687,447

## Abstract

Project Summary
The vast heterogeneity of genetic and epigenetic features both among samples from any cancer type and
within individual tumors has been documented with increasing resolution. Of note, intratumoral heterogeneity,
which fuels clonal evolution and generates treatment resistance, has been identified as the foremost obstacle
to lasting cure. This is true of chronic lymphocytic leukemia (CLL), an initially indolent malignancy of mature B
cells which inevitably becomes more aggressive over time, and whose clinical course is highly variable across
individuals. Despite the recent approval of highly potent drugs (i.e. ibrutinib, idelalisib) that target key CLL
pathways, drug resistance—sometimes associated with highly aggressive relapse while on treatment—has
been reported. The challenges presented by this disease heterogeneity mandate large-scale interdisciplinary
approaches to link genomic features with cellular behavior so that effective personalized treatments can be
devised. Our hypothesis is that CLL has heterogeneous yet coherent genomic alterations leading to distinct
phenotypic behaviors, subject to evolutionary selective pressures, which impact individual disease trajectories.
The members of the proposed Program have a successful track record of collaborating together to make
landmark contributions to our understanding of CLL. Despite our growing knowledge about CLL and the
expanding armamentarium of effective therapeutics targeting it, the next quantum leap in our understanding of
this disease will require network-level integration across data layers in well-powered series to comprehensively
map the circuitry of CLL (Projects 1, 2), and systematic approaches to evaluate the impact of genomic
alterations on prognosis and response to therapy (Projects 2, 3). Certainly, conventional approaches to
functionally study genetic lesions of CLL have been limited by the lack of faithful cell lines and mouse models
and by the widely acknowledged difficulties in genetically manipulating primary CLL cells. Through major
innovations in approaches to dissect CLL, spearheaded by each Project Leader and ranging from
computational to functional genetic and non-genetic based readouts in primary human B cells, we are well-
poised to synergize together to address clinically relevant questions in CLL. These initiatives are strongly
supported by the joint expertise of the Core Leaders and are expected to inform us on the rational design of
the next generation of personalized and curative therapies for CLL.

## Key facts

- **NIH application ID:** 10005126
- **Project number:** 5P01CA206978-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Catherine Ju-Ying Wu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,687,447
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005126

## Citation

> US National Institutes of Health, RePORTER application 10005126, Comprehensive dissection of the CLL genome and phenome to improve patient outcomes (5P01CA206978-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10005126. Licensed CC0.

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