March 24, 2021.

A collaborative effort between the labs of Charles Mullighan, St Jude Children’s Research Hospital, and Benjamin Ebert, Dana-Farber Cancer Institute, to identify the driving factors in acute erythroid leukemia was recently published in the journal Blood. Acute erythroid leukemia (AEL) is a rare cancer that is characterized by proliferation of leukemic erythroblasts in the bone marrow.  Although recurrent gene mutations have been identified in AEL, the effect of these genetic alterations on cancer initiation and progression was unclear. In the current study, the authors selected 10 genes (Trp53, Tet2, Dnmt3a, Asxl1, Ezh2, Stag2, Bcor, Ppm1d, Rb1, and Nfix) to target in mouse hematopoietic stem and progenitor cells (HSPCs) using 6 differential gRNA pools. The transduced HSPCs were transplanted into mice and subsequent leukemic transformation was observed. Analysis of the cells revealed that combinatorial disruption of Bcor, Trp53, Dnmt3a, Rb1, and Nfix resulted in AEL, and the leukemic cells also acquired secondary mutations in transcription factors and signaling genes. The newly established erythroleukemia mouse model was used to find therapeutic strategies against AEL. Talazoparib (PARP-inhibitor) and Decitabine (demethylating drug) showed efficacy against leukemic cells with Trp53 and Bcor mutations. In addition, CDK7/9 inhibitors were shown to mediate an anti-tumor response in AEL cells with mutations in Trp53, Bcor, and Dnmt3a.

For more information, see:
Iacobucci, I., et al. (2021) Modeling and targeting of erythroleukemia by hematopoietic genome editing. Blood 137: 1628–1640. https://doi.org/10.1182/blood.2020009103

Zhang, J.P., Tao Cheng, T. (2021) Modeling acute erythroid leukemia via CRISPR. Blood 137: 1565–1567. https://doi.org/10.1182/blood.2020010544

Questions? Email: crispr@amsterdamumc.nl