Fig. 1: Complex chromosomal rearrangements drive karyotype heterogeneity in CK-AML.

a, Schematic study layout of single-cell multiomics profiling with scNOVA and CITE-seq, applied to eight samples from patients with primary CK-AML at initial sampling, five matching PDXs and two matching refractory or relapse samples. scNOVA was used to assess structural variant (SV) landscapes and nucleosome occupancy (NO). CITE-seq was applied to assess transcriptomes and cell-surface proteomes. Panel a created with BioRender.com. b, Karyotype heatmap of 542 single cells arranged using Ward’s method for hierarchical clustering of structural variant genotypes in eight patients at initial sampling. c,d, Strand-specific read depth of a representative single cell from CK282 showing clustered deletions, inverted duplications and inversions along a single homolog chromosome 12 (c) and chromosome 17 (d), resulting from clonal chromothripsis. Reads denoting somatic structural variants, discovered using scTRIP, were mapped to the Watson (orange) or Crick (green) strand. Gray indicates single-cell IDs. e, Circos plot illustrating complex rearrangements and translocations involving multiple chromosomes, assessed by OGM from a PDX of CK282. Chromosomes (outside of the circular plot) and chromosomal rearrangements are shown as arcs connecting the two relevant genomic regions in the middle. The data are represented as follows (starting from the outer ring): structural variants, copy-number variation and translocations. f, Chromosome view of 3q in HIAML85 and CK397 with mapping of segments by Strand-seq (top) and OGM (bottom) showing inversions spanning parts of the q arm. In Strand-seq, composite reads shown were taken from all informative cells in which reads could be phased (Watson–Crick or Crick–Watson configuration). The black vertical dotted lines indicate the breakpoint positions of inversions. In OGM, de novo genome maps (blue) are aligned to the reference genome (yellow) with gray lines showing connecting genomic segments. g, Karyotype heterogeneity in eight samples from patients with CK-AML based on structural variant burden (bottom) and its s.d. (top). Each gray dot represents a single cell in CK282 (n = 76), CK295 (n = 41), CK397 (n = 70), CK349 (n = 91), P9D (n = 44), HIAML47 (n = 91), D1922 (n = 63) and HIAML85 (n = 66); Point ranges were defined by minima = mean − 2× s.d., maxima = mean + 2× s.d., point = mean. Dup, duplication; InvDup, inverted duplication; Tra, translocation.