# Therapeutic potential of Cpf1-based gene editing for myeloproliferative neoplasms

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $208,670

## Abstract

Project Summary
Myeloproliferative neoplasms (MPNs) are groups of hematological diseases overproducing blood cells. A
single gain-of-function point mutation in JAK2 gene (1849GèT in exon 14), named JAK2V617F, has been
identified in the majority of MPN patients. MPNs are transplantable with hematopoietic stem cells (HSCs)
carrying JAK2V617F gene. While JAK2 inhibitors are promising drugs for inhibiting MPN-induced complications,
they cannot cure MPNs. Until now, allogeneic HSC transplantation (allo-HSCT) has been the only curative
treatment for MPNs. However, a majority of patients suffer from a shortage of HLA-matched donors and some
allo-HSCT recipients develop graft-versus-host disease (GvHD) that is a prominent cause of death and has
important implications on immunosuppressive medications. Hence, it would be of immense clinical benefit to
develop safe gene editing strategies to inactivate JAK2V617F mutant HSCs from MPN patients containing both
healthy and mutant HSCs. If these strategies are successful, it will be possible to curatively treat MPN patients
using autologous HSC transplantation (auto-HSCT), without a need to find a matching donor in the patient's
family and to avoid the risk of GvHD. In this proposal, we hypothesize that JAK2V617F-specific guide RNA
(gRNA) will direct Cpf1 nuclease-mediated DNA cleavage of JAK2V617F gene, leading to the inactivation of
MPN-initiating HSCs. To test this hypothesis, we will pursue two specific aims: i) Inactivation of MPN cells by
removing JAK2V617F exon 14 using CRISPR/Cpf1 gene editing, and ii) Assess the therapeutic potential of
CRISPR/Cpf1-based auto-HSCT in a xenograft model of MPN. In aim 1, we will assess the effects of
JAK2V617F-specific CRISPR/Cpf1 gene editing on the colony-forming capacity of MPN cell lines and on ex vivo
inactivation of HSCs-harboring JAK2V617F in MPN CD34+ HSC pool. In aim 2, we will first generate xenograft
models of MPN by engrafting MPN patient-derived CD34+ cells. Next, we will test the therapeutic potential of
high-dose chemotherapy followed by auto-HSCT with MPN HSCs edited by JAK2V617F-CRISPR/Cpf1 gene
editing. These studies will demonstrate the feasibility of CRISPR/Cpf1 gene editing-based auto-HSCT joint with
high-dose chemotherapy for the treatment of patients with MPNs. Regarding expected outcomes, we anticipate
that we will demonstrate effective gene editing strategies for inactivating MPN-initiating HSCs. Such results will
have an important positive impact because these approaches are translatable for developing gene editing-
based auto-HSCT therapeutic strategy for MPN patients and possible for other hematopoietic malignancies.

## Key facts

- **NIH application ID:** 9931187
- **Project number:** 5R21CA234866-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** WEN-SHU WU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $208,670
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931187

## Citation

> US National Institutes of Health, RePORTER application 9931187, Therapeutic potential of Cpf1-based gene editing for myeloproliferative neoplasms (5R21CA234866-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9931187. Licensed CC0.

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