Induction of a renal developmental cell state is associated with chemotherapy resistance in favorable-histology Wilms tumor [CUT&Tag]
Children with favorable histology Wilms tumor (FHWT) who experience disease relapse or whose tumors exhibit blastemal predominance after chemotherapy often have poor outcomes. We established a FHWT patient-derived xenograft model, KT-47, that exhibited blastemal predominance after chemotherapy treatment with vincristine, actinomycin, and doxorubicin (VAD) and ultimately developed complete resistance to VAD after serial exposures to this combination. Histologic analyses and comprehensive multi-omics approaches were used to evaluate changes associated with resistance. CUT&TAG identified increased transcriptionally active H3K4me3 at stem cell and nephrogenesis gene promoters among the most different regions in KT-47 resistant compared to the KT-47 pretreatment model including the HOXB cluster, HOXC cluster, MYCN, SIX2, IGF2, CITED1, and OSR1. In contrast, decreased H3K27me3 was identified at HOX gene cluster and nephrogenesis gene promoter regions. The most significantly upregulated transcript and protein that associated with resistance in KT-47 was the let7 microRNA processor LIN28B. LIN28B upregulation was associated with copy number gain at MYCN and plasticity of cancer cells marked by open chromatin at the LIN28B locus rather than expansion of a minor subclone expressing LIN28B present in the original primary tumor material. The stem cell-associated multidrug resistance protein ABCB1 was upregulated in epithelial cells in association with an inter-chromosomal interaction between chromosomes 1 and 7. The impact of these findings at MYCN, LIN28B, and ABCB1 were validated in additional WT models and samples. Overall, these results support de-differentiation of FHWT cancer cells to a stem-like state which is associated with chemotherapy resistance. Targeting epigenetic modifiers that modulate differentiation of cancer cells with a stem-like phenotype could be a future treatment strategy in chemotherapy resistant FHWT. Overall design: CUT&TAG analysis of KT-47 pretreatment (KT-47PT) and KT-47 resistance (KT-47R1) samples. KT-47 pretreatment received no chemotherapy in the xenograft model.  KT-47R1exhibited complete resistance to vincristine, actinomycin-D, and doxorubicin.