# CCRL2 as a Regulator of Growth and Novel Target in Myelodysplastic Syndrome

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $171,720

## Abstract

Project Summary
High-risk myelodysplastic syndrome (MDS) arises from malignant primitive cells that are resistant to current
therapies. These cells exhibit a growth benefit in the MDS microenvironment and their elimination is challenging
due to the lack of targetable markers distinguishing them from healthy primitive cells. We found that men with
MDS and myeloproliferative neoplasms (MPN) have worse survival and higher disease burden in their primitive
cells compared to women. To shed light into these sex differences, we evaluated the expression of known
androgen receptor (AR) target genes in MDS/MPN samples. We found that one of the top AR-regulated genes,
CCRL2, is overexpressed in primitive cells from MDS patients. CCRL2 is an atypical chemokine receptor as it
lacks G-protein binding domain, is internalized via endocytosis and its C-terminal region is required for its surface
localization. Our published results showed that CCRL2 induces MDS growth and activates JAK2 highlighting this
receptor as a potential target in MDS. CCRL2 knockdown suppresses growth-related pathways, most
prominently transferrin receptor (TFRC) and E2F targets. However, as CCRL2 lacks signaling domains, the exact
mechanism is unclear. We hypothesized that CCRL2 interacts with TFRC in early endosomes and activates it
while CDK/E2F is regulated by CCRL2 via JAK2. We also hypothesize that CCRL2 C-terminal region is essential
for its oncogenic properties. We found that CCRL2 deletion sensitizes MDS cells to azacitidine, the most
commonly used MDS therapy. Inhibition of JAK2, a CCRL2 target increases azacitidine efficacy in CCRL2 wild-
type but not in CCRL2 knockdown cells. Thus, JAK2 may mediate the CCRL2-regulated azacitidine resistance.
This also suggests that targeting other CCRL2-regulated pathways can be selectively effective against CCRL2-
expressing cells. Thus, we hypothesize that inhibition of CCRL2-regulated pathways or agents suppressing
CCRL2 levels are toxic against CCRL2-expressing cells and can increase azacitidine efficacy. In Aim 1 we will
confirm the induction of TFRC growth-related activity by CCRL2, define JAK2 role in CCRL2-mediated growth
pathways regulation and determine the involvement of CCRL2 C-terminal region in its growth effects by
performing immunofluorescence, proteomics, and CCRL2 gene editing. In Aim 2 we will confirm the implication
of JAK2/STAT in the CCRL2-mediated azacitidine resistance and discover other agents with selective efficacy
against CCRL2-expressing cells by performing drug and CRISPR-Cas9 knockout screens. Selected agents will
be combined with azacitidine in an inducible-CCRL2 MDS xenograft model. These studies will provide the PI the
opportunity to gain critical skills and expertise to study the molecular biology of MDS growth with emphasis in
the role of CCRL2 and discover novel targeted therapies for this disease. These objectives will be accomplished
through formal coursework, scientific programing, and direct mentorship b...

## Key facts

- **NIH application ID:** 10832117
- **Project number:** 5K08HL168777-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Theodoros Karantanos
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $171,720
- **Award type:** 5
- **Project period:** 2023-04-25 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832117

## Citation

> US National Institutes of Health, RePORTER application 10832117, CCRL2 as a Regulator of Growth and Novel Target in Myelodysplastic Syndrome (5K08HL168777-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10832117. Licensed CC0.

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