ETV6-NCOA2 fusion induces T/Myeloid mixed-phenotype leukemia by transformation of non-thymic hematopoietic progenitors.
Hila FishmanShreyas MadiwaleIfat GeronVase BariWouter Van LoockeYael KirschenbaumItamar GanmoreEitan KuglerAvigail Rein-GilGilgi FriedlanderGinette SchibyYehudit BirgerSabine StrehlJean SoulierBirgit KnoechelAdolfo FerrandoSharon Noy LotanArnon NaglerJames C MulloyPieter Van VlierbergheShai IzraeliPublished in: Blood (2021)
Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation, creating ETV6-NCOA2 fusion, with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone-marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1 activating mutations. Similarly, co-transduction of human cord-blood CD34+ progenitors with ETV6-NCOA2 and a non-transforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern was similar to that of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to de-repression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse non-thymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at early-immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early-immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.
Keyphrases
- bone marrow
- acute lymphoblastic leukemia
- acute myeloid leukemia
- gene expression
- mesenchymal stem cells
- dendritic cells
- endothelial cells
- poor prognosis
- high glucose
- induced apoptosis
- signaling pathway
- dna methylation
- diabetic rats
- type diabetes
- genome wide
- cord blood
- cell proliferation
- copy number
- immune response
- stem cells
- drug induced
- insulin resistance
- cell therapy
- cell death