Modeling de novo leukemogenesis from human cord blood with MN1 and NUP98HOXD13

Abstract

Key Points• MN1 promotes self-renewal and inhibits differentiation of CD34 1 cord blood cells in vitro.• De novo leukemogenesis is engineered by MN1 and NUP98HOXD13 expression in cord blood cells.

MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

“…However, cotransduction of MN1 and NUP98-HOXD13 resulted in full transformation to AML. This confirms the central role of homeobox transcription factors and their collaboration with MN1 in AML leukemogenesis (17).…”

GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo

“…Interestingly, absence or low expression of GPR56 was not only associated with MLL-rearranged AML, but also with inv(16) and t(8;21), 2 cytogenetic aberrations associated with favorable prognosis, 30 which are known to rarely engraft in immunocompromised mice 15 and were therefore not assessed in our study. Whereas high GPR56 expression had been linked to EVI1-mutated AML before, 28 we found significant enrichment also for other genetic groups associated with poor prognosis, including FLT3-ITD and mutations in RUNX1 and TP53, 35 suggesting that GPR56 might be part of a common stem cell network induced by different mutational events.…”

“…15 Ten weeks after transduction, we detected GPR56 expression by quantitative reverse-transcription polymerase chain reaction and flow cytometry only in double transduced ND131MN1 cells, which caused leukemia when injected in immunocompromised mice, whereas single-transduced ND13 cells lacked leukemogenic potential in vivo and maintained a CD34 2 GPR56 2 phenotype (supplemental Figure 9A- …”

UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells

“…1 umbilical cord blood cells transduced with MN1 1 ND13 oncogenes (MN1/ND13 cells) 22 were maintained in Iscove modified Dulbecco medium supplemented with 15% FCS, 1% glutamine, 100 U/mL penicillin, 100 mg/mL streptomycin, 10 ng/mL IL-3, 10 ng/mL granulocyte-macrophage colonystimulating factor (GM-CSF), 10 ng/mL Flt-3, 10 ng/mL stem cell factor (SCF), and 10 ng/mL thrombopoietin. Foxp3 fixation and permeabilization buffers, CellTrace 450, CellTrace 670, anti-human CD56 conjugated to allophycocyanin (APC), anti-human CD34 conjugated to APC (clone 4H11), anti-human IFN-g conjugated to e-Fluor 450, and anti-human CD69 conjugated to fluorescein isothiocyanate (FITC) were obtained from EBiosciences (San Diego, CA).…”

“…22 Four weeks after implantation of MN1/ND13 cells, engraftment was verified by flow cytometry (Figure 7A), and mice were i.v. injected with PBS, T cell-depleted healthy human PBMCs (3 310 6 cells), or T cell-depleted PBMCs exposed ex vivo to UV-HSV-1 (3 3 10 6 cells; 0.1 pfu/PBMC; 16 hours).…”