Zhaohui Ye, PhD – Johns Hopkins

Project Title:

Precise Genome Editing for Targeting Malignant Clones in MPNs

Focus Area(s):

Targeting the Malignant JAK2 clone, Gene editing applied to MPNs

Question/ Issue:

This projects hopes to prove that CRISPR gene editing can provide a platform for pre-clinical development of new therapies.

Project Description:

The researchers aim to identify common pathways in different types of MPNs and to eliminate JAK2 mutation in mouse models using CRISPR technology.

What we can expect to learn:

The goal is to determine whether targeting the malignant MPN clone by CRISPR is effective in reducing the allele burden of the disease. They also will determine if there is a potential for combining other anti-cancer drugs with this approach.

Project Abstract:

The overarching goal of this proposal is to apply the latest genome editing technologies in the development of therapeutic options for MPNs. Built on our research team’s experience in MPN gene expression analysis, disease modeling and genome editing, we will create cellular genetic models of JAK2 and CALR mutations using isogenic human induced pluripotent stem cells. Differential gene regulation induced by each of these two most prevalent yet mutually exclusive somatic mutations will be first determined by global gene expression analyses. Comparative study will then determine the common pathways that are dysregulated in MPNs and potential new targets for therapeutic development. In parallel, we also aim to establish a CRISPR-mediated approach to target and eliminate the malignant MPN clones that contain JAK2-V617F.

Chimeric JAK2-V617F mouse models will be used to evaluate the efficiency of in vivo targeting of the mutant clones and its effect on JAK2 allele burden and potential disease phenotypes. We will also evaluate the potential synergistic effects of other anti-cancer drugs in this approach. Completion of this study will provide a proof-of-principle of such strategy and a platform for pre-clinical development.