Establishment of a High‐risk MDS/AML Cell Line YCU‐AML1 and its Xenograft Model Harboring t(3;3) and Monosomy 7

Abstract

Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with both inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 defines an extremely aggressive myeloid cancer whose molecular pathogenesis and optimal therapeutic strategy still remain unclear. We established a new MDS/AML cell line, YCU-AML1, and its patient-derived xenograft (PDX) model from a high-risk MDS patient who later transformed into AML harboring both t(3;3)(q21;q26.2) and monosomy 7. YCU-AML1 cells propagated in co-culture system with stromal cells in granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent manner. CD34+ bone marrow cells derived from our PDX model showed high EVI1 and low GATA2 expression. Moreover, mutational profile of our MDS/AML model was consistent with recently published mutational spectrum of myeloid malignancies with inv(3)/t(3;3). These data suggest that YCU-AML1 cells and its MDS/AML model strongly mimics a high-risk human myeloid cancer with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 in terms of both clinical phenotype and molecular basis. We believe our model can be used as a feasible tool to further explore molecular pathogenesis and novel treatment strategy of high-risk MDS/AML with t(3;3)(q21;q26.2) and monosomy 7.

Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

“…For example, the inv(3)/t(3;3) AML cell lines HNT-34 and YCU-AML1 harboring SF3B1 K700E heavily express this variant EVI1 isoform ( Figure 4C ). 30,31 Expression of several SF3B1 mutations (K700E, K666N, and G740E), but not WT SF3B1 , into K562 cells similarly resulted in the aberrant EVI1 isoform generation (supplemental Figure 6A). Sanger sequencing of this isoform verified that this splice variant results in the introduction of 18 nucleotides inserted between exons 12 and 13 of the EVI1 transcript, at the very 3′ end of intron 12 ( Figure 4D ).…”

Progress in construction of mouse models to investigate the pathogenesis and immune therapy of human hematological malignancy

“…The MDS PDX model is constructed from MDS stem cells from patients ( 77 ), which reproduces human myeloid differentiation rather than lymphoid differentiation ( 78 ). By implanting high-risk MDS cells into the PDX model ( 79 ), researchers can study whether there are other abnormalities in model-derived bone marrow stem cells ( 80 ). However, the success rate of implanting low-risk MDS in NSG mice is still low, which needs to be further resolved ( 81 ).…”