George Church, PhD, Harvard Medical School

George Church, PhD, Harvard Medical School

George Church MPN ResearcherProject Title:

Establishment of isogenic human induced pluripotent stem cell (hiPSC) lines containing CRISPR engineered MPN mutations

Focus Area(s):

Targeting the Malignant JAK2 clone, Gene editing applied to MPNs, Other New Mechanisms of Action

Question / issue:

Common mutations in MPN have been identified; however, studying the exact effect of these mutations has been complicated by variations in the genetic background across patient samples and species differences in mouse models.

Project Description:

George Church's lab will use CRISPR gene editing to engineer the most common MPN mutations into human induced pluripotent stem cells. These cells, which will be genetically identical except for the mutation, can then be developed into human pluripotent stem cells and compared to examine the downstream consequences of these mutations.

These materials and information will be shared with other MPN researchers. The samples will come from patients who have volunteered for the Church lab's Personal Genome Project and thus agreed for any results to be openly shared with the public.

What we can expect to learn:

From this work, researchers will be able to examine how MPNs progress from an initial mutation. These mutated cell lines will be a common available resource to the MPN research community, who can analyze the effect of the MPN mutation separate from other human genetic differences. Additionally, the project will explore the potential use of CRISPR gene editing as a future gene therapy.

Expanded Project Abstract:

While extensive analysis has been done to identify the most common mutations in MPN, efforts to study the causal effect of these mutations have been complicated by differences in genetic background between patient samples or species differences in mouse models. This team will use the new CRISPR / Cas9 gene editing technology to engineer the most common MPN mutations into human iPSC lines, creating a renewable controlled source of genetically matched human hematopoietic progenitor cells. Using transcriptome analysis and functional assays for erythroid development, these isogenic cells will be compared to identify the downstream consequences of these hypothesized driver mutations. Finally, they will distribute these characterized lines as a scientific resource to collaborating MPN researchers. Since these iPSC will be derived from Personal Genome Project volunteers, their genomes and cell lines have not only been sequenced, but they are also fully consented to be publicly available at With this isogenic set of hiPSC bearing common MPN mutations, MPN researchers will be able to examine the mechanism for how these mutations drive MPN progression.

In addition, this team will also explore the use of CRISPR gene editing to specifically target existing MPN mutations as an initial proof of principle for future gene therapies.

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