Summary

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.

Overall design

The design for the 10x sort was: 8700 Lin-CD71+CD235a+ and 8700 Lin-CD71-CD235a- single cells were sorted from two human AEL samples and 15000 Lin-CD45. 1-GFP- single cells were sorted from two KLG-E mice. Libraries were preparing using the chromium single cell 3’ reagent kits v2 (10x Genomics, California USA) according to manufacturer’s protocol.

Contributors

Cristina Di Genua 1, Simona Valletta 1, Mario Buono 1, Bilyana Stoilova 2, Connor Sweeney 2, Alba Rodriguez-Meira 1, Amit Grover 1, Roy Drissen 1, Yiran Meng 1, Ryan Beveridge 1, Zahra Aboukhalil 2, Dimitris Karamitros 2, Mirjam E Belderbos 3, Leonid Bystrykh 4, Supat Thongjuea 5, Paresh Vyas 2, Claus Nerlov 6

Contact

claus.nerlov@imm.ox.ac.uk.(Claus Nerlov)