A CRISPR-based platform to model AML progression using primary human cells

Transformation from clonal hematopoiesis to leukemia is incompletely understood. Neonates with trisomy 21 (Down syndrome) exhibit pre-leukemic transient abnormal myelopoiesis (TAM) caused by somatic mutations in GATA1 gene. TAM clonally evolves to myeloid leukemia in Down syndrome (ML-DS) upon acquisition of secondary mutations. Thus, TAM and ML-DS are genetically simple models, where samples from two temporally separable and ascertainable stages in leukemogenesis can be studied. We established a virus-free CRISPR platform utilising the Ribonucleoprotein RNP/Cas9 system to introduce GATA1 mutation and additional mutations in primary human fetal liver hematopoietic stem and progenitor cells (hFLCs). We succeeded in mimicking the progression from clonal hematopoiesis to full-blown leukemia, in vitro and in vivo, as seen in Down syndrome leukemogenesis. Our newly developed human system to investigate leukemic progression offers a unique platform to rewire the synergy between founder genetic aberrations and passenger events and hence make decisive steps towards understanding the malignant transformation from clonal hematopoiesis to frank leukemia.

Publication History

Article published online:
17 May 2022