# Defining Epidrivers of CLL Evolution in Response to Targeted Therapy

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $480,304

## Abstract

Cancer's ability to evolve in response to the pressures exerted by therapy is the single most common cause
of therapeutic failure and poor clinical outcomes across most cancer types. We studied the evolution of
chronic lymphocytic leukemia (CLL), which epitomizes the challenge posed to modern oncology by cancer
evolution: despite effective therapies, the disease invariably recurs. We have measured intra-tumoral
diversity, using genomic and epigenomic data, and have shown that evolution with therapy is virtually
universal (Cell, 2013; Cancer Cell, 2014; Nature, 2015; Nature Communications, 2016).
A major, emerging theme in oncology is that tumor evolution to resistance may also follow non-genetic routes.
Specifically, cell persistence, lineage plasticity, and micro-environmental interactions are all non-genetically
determined phenotypes, which are heritable and enable tumors to evolve and evade therapeutic attack. In
CLL, we have shown that these mechanisms are highly active in resistance to ibrutinib therapy, a leading
targeted agent (Nature Communications, in press). Unlike genetic resistance, we currently lack even a
rudimentary framework on how to therapeutically target these mechanisms. Therefore,we aim to dissect how
epigeneticand micro-environmental heterogeneity produce the cancer's ability to evolve and relapse.
First,through the application of novel statistical inference to serial DNA methylation (DNAme) patient sample
profiling,
we
will
define
positively
selected
DNAme
changes
–
epidrivers
–
that
result
in
cell
persistence.
We
will
validate
candidate
epidrivers
through
precision
epigenetic
editing,
in
order
to
causally
link
epidrivers
with
the
persistence
phenotype.
We
will
integrate
the
DNAme
profiles
with
transcriptional
and
clonal
identity
by
applyingour innovative, multi-modality, single-cell platform.
Second,histone code disruption and aberrant transcription factor (TF) expression have heritable evolutionary
potential,
and
may
be
causes
of
lineage
plasticity.
To
identify
epidrivers
of
lineage
plasticity,
we
will
perform
combinatorial histone mapping in serial samples from patients with Richter's transformation. We will
complementthe patient sample studies with Screen-seq – a method to link TF and histone modifiers with the
abilityto evolve to high-grade lymphoma under therapeutic pressure.
Third,
our
results
show
that
cells
with
resistance
mutations
enable
the
growth
of
cells
without
the
mutation
through
micro-environmental
collaboration.
To
interrogate
the
co-evolution
of
CLL
and
its
micro-environment,
we
will
apply
single-cell
droplet
RNAseq
to
serial
lymph
node
samples
from
patients
undergoing
ibrutinib
therapy.
Our
multi-modality,
novel
single-cell
droplet
platform
will
allow
us
to
capture
clonal
identity,
together
withwhole transcriptome profiling, across CLL clones and neighboring, interacting immune cells.
Collectively, this novel set of tools will map the epigenetic and environmental evolutionary potential of
CLL and nomina...

## Key facts

- **NIH application ID:** 9999527
- **Project number:** 5R01CA229902-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dan Landau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,304
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999527

## Citation

> US National Institutes of Health, RePORTER application 9999527, Defining Epidrivers of CLL Evolution in Response to Targeted Therapy (5R01CA229902-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999527. Licensed CC0.

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