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Genome editing to model and reverse a prevalent mutation associated with myeloproliferative neoplasms

Ron Baik, View ORCID ProfileStacia K. Wyman, View ORCID ProfileShaheen Kabir, View ORCID ProfileJacob E. Corn
doi: https://doi.org/10.1101/855452
Ron Baik
1Innovative Genomics Institute, University of California, Berkeley, CA 94720
2Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
3Department of Pediatrics, Stanford University, Stanford, CA 94305
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Stacia K. Wyman
1Innovative Genomics Institute, University of California, Berkeley, CA 94720
2Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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Shaheen Kabir
1Innovative Genomics Institute, University of California, Berkeley, CA 94720
2Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
4Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158
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  • For correspondence: Jacob.corn@biol.ethz.ch shaheen.kabir@ucsf.edu
Jacob E. Corn
1Innovative Genomics Institute, University of California, Berkeley, CA 94720
2Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
5Department of Biology, ETH Zurich, Switzerland
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  • For correspondence: Jacob.corn@biol.ethz.ch shaheen.kabir@ucsf.edu
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Abstract

Myeloproliferative neoplasms (MPNs) cause the over-production of blood cells such as erythrocytes (polycythemia vera) or platelets (essential thrombocytosis). JAK2 V617F is the most prevalent somatic mutation in many MPNs, but previous modeling of this mutation in mice relied on transgenic overexpression and resulted in diverse phenotypes that were in some cases attributed to expression level. CRISPR-Cas9 engineering offers new possibilities to model and potentially cure genetically encoded disorders via precise modification of the endogenous locus in primary cells. Here we develop “scarless” Cas9-based reagents to create and reverse the JAK2 V617F mutation in an immortalized human erythroid progenitor cell line (HUDEP-2), CD34+ adult human hematopoietic stem and progenitor cells (HSPCs), and immunophenotypic long-term hematopoietic stem cells (LT-HSCs). We find no overt in vitro increase in proliferation associated with an endogenous JAK2 V617F allele, but co-culture with wild type cells unmasks a competitive growth advantage provided by the mutation. Acquisition of the V617F allele also promotes terminal differentiation of erythroid progenitors, even in the absence of hematopoietic cytokine signaling. Taken together, these data are consistent with the gradually progressive manifestation of MPNs and reveals that endogenously acquired JAK2 V617F mutations may yield more subtle phenotypes as compared to transgenic overexpression models.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 26, 2019.
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Genome editing to model and reverse a prevalent mutation associated with myeloproliferative neoplasms
Ron Baik, Stacia K. Wyman, Shaheen Kabir, Jacob E. Corn
bioRxiv 855452; doi: https://doi.org/10.1101/855452
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Genome editing to model and reverse a prevalent mutation associated with myeloproliferative neoplasms
Ron Baik, Stacia K. Wyman, Shaheen Kabir, Jacob E. Corn
bioRxiv 855452; doi: https://doi.org/10.1101/855452

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