- Jiang, Qingfei;
- Isquith, Jane;
- Ladel, Luisa;
- Mark, Adam;
- Holm, Frida;
- Mason, Cayla;
- He, Yudou;
- Mondala, Phoebe;
- Oliver, Isabelle;
- Pham, Jessica;
- Ma, Wenxue;
- Reynoso, Eduardo;
- Ali, Shawn;
- Morris, Isabella Jamieson;
- Diep, Raymond;
- Nasamran, Chanond;
- Xu, Guorong;
- Sasik, Roman;
- Rosenthal, Sara Brin;
- Birmingham, Amanda;
- Coso, Sanja;
- Pineda, Gabriel;
- Crews, Leslie;
- Donohoe, Mary E;
- Venter, J Craig;
- Whisenant, Thomas;
- Mesa, Ruben A;
- Alexandrov, Ludmil B;
- Fisch, Kathleen M;
- Jamieson, Catriona
Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.