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DOI: 10.1055/s-0042-1748743
HiPSC disease modelling to study leukemia development in HAX1 vs ELANE associated congenital neutropenia
Severe congenital neutropenia (CN) is a pre-leukemic syndrome with a high risk of developing MDS/AML associated with the acquisition of CSF3R and RUNX1.
We established a model for step-wise leukemia progression in HAX1- and ELANE-CN using iPSC-based hematopoietic differentiation in combination with CRISPR/Cas9-mediated gene editing of iPSCs. We compared HAX1 and ELANE-CN phenotypes and the role of missense vs non-sense RUNX1 mutations in leukemogenesis. We identified BAALC upregulation as a key leukemogenic event and BAALC KO restored granulocytic differentiation. HAX1- and ELANE-CN/AML iPSC-derived CD34+ cells showed reduced granulocytic differentiation and increased proliferation.
RNA-seq analysis of iPSC-derived CD34+ cells showed high similarity between ELANE- and HAX1-CN/AML revealing features of RUNX1 mutant leukemia, upregulation of inflammatory response and MYC targets. We also identified GATA1/2 transcription factors, as well as HIPK2 and MAPK1,3,14 kinases as main regulators of DEGs.
In summary, we identified shared and mutation-specific leukemogenic signaling pathways in CN regarding the inherited mutation status or based on the type of acquired RUNX1 mutations.
Publication History
Article published online:
17 May 2022
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