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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Foßelteder, J; Pabst, G; Sconocchia, T; Schlacher, A; Auinger, L; Kashofer, K; Beham-Schmid, C; Trajanoski, S; Waskow, C; Schöll, W; Sill, H; Zebisch, A; Wölfler, A; Thomas, D; Reinisch, A.
Human gene-engineered calreticulin mutant stem cells recapitulate MPN hallmarks and identify targetable vulnerabilities.
Leukemia. 2023; 37(4): 843-853.
Doi: 10.1038/s41375-023-01848-6
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- Leading authors Med Uni Graz
- Foßelteder Johannes
- Reinisch Andreas
- Co-authors Med Uni Graz
- Auinger Lisa
- Beham-Schmid Christine
- Kashofer Karl
- Pabst Gabriel
- Schlacher Angelika
- Schöll Wolfgang
- Sconocchia Tommaso
- Sill Heinz
- Trajanoski Slave
- Wölfler Albert
- Zebisch Armin
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- Abstract:
- Calreticulin (CALR) mutations present the main oncogenic drivers in JAK2 wildtype (WT) myeloproliferative neoplasms (MPN), including essential thrombocythemia and myelofibrosis, where mutant (MUT) CALR is increasingly recognized as a suitable mutation-specific drug target. However, our current understanding of its mechanism-of-action is derived from mouse models or immortalized cell lines, where cross-species differences, ectopic over-expression and lack of disease penetrance are hampering translational research. Here, we describe the first human gene-engineered model of CALR MUT MPN using a CRISPR/Cas9 and adeno-associated viral vector-mediated knock-in strategy in primary human hematopoietic stem and progenitor cells (HSPCs) to establish a reproducible and trackable phenotype in vitro and in xenografted mice. Our humanized model recapitulates many disease hallmarks: thrombopoietin-independent megakaryopoiesis, myeloid-lineage skewing, splenomegaly, bone marrow fibrosis, and expansion of megakaryocyte-primed CD41+ progenitors. Strikingly, introduction of CALR mutations enforced early reprogramming of human HSPCs and the induction of an endoplasmic reticulum stress response. The observed compensatory upregulation of chaperones revealed novel mutation-specific vulnerabilities with preferential sensitivity of CALR mutant cells to inhibition of the BiP chaperone and the proteasome. Overall, our humanized model improves purely murine models and provides a readily usable basis for testing of novel therapeutic strategies in a human setting.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Animals - administration & dosage
- Mice - administration & dosage
- Calreticulin - genetics, metabolism
- Janus Kinase 2 - genetics
- Myeloproliferative Disorders - genetics
- Mutation - administration & dosage
- Hematopoietic Stem Cells - metabolism
- Primary Myelofibrosis - genetics, metabolism