Fig. 4: Timing and fitness of BCR::ABL1-driven clonal expansion.
From: Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia
a,b, Bar plots show rtreefit-based latency in years (a) and phylofit-based (Methods) annualized growth rate as a percentage (b), with patients ordered by age at diagnosis. The height of the bars and vertical lines indicate the posterior median and equal-tailed 95% credibility intervals, respectively. Mutant transcript type and intronic versus exonic out-of-frame BCR and ABL1 breakpoints are depicted along top strips. An asterisk * indicates non-reciprocal BCR::ABL1 translocation with der(9) loss. Time (in months) to major molecular remission (MMR) (BCR::ABL1/ABL1 ratio less than 0.1% by International Standards) is shown underneath. NR, not reached MMR. **Follow-up times for PD57334 and PD57335 were 23 and 21 months, respectively. c, Relationship between inferred BCR::ABL1 acquisition (years) and annualized growth rate (%) per year for the BCR::ABL1-positive clone. The dots are based on the posterior median estimates of S and latency and the fitted line and 95% confidence interval (grey band) is derived from the linear model log(log(1 + S)) ~ log(latency). d, Estimated doubling time \(\left(=\frac{1}{{\log }_{2}(1+S)}\right)\) versus time from BCR::ABL1-induced clonal expansion to diagnosis (‘latency’). The fitted line and 95% confidence interval (grey band) is derived from the linear model used in c. e,f, Fish (e) and tree plot (f) describing the broad architecture of clones found at advanced phase (81.3 years) and blast phase (81.7 years) in PD60243. ABL1 mutant clones were confirmed to be in different cells using read based phasing. Tree reconstructions predict a median of 2 (range 1–3) ABL1 mutant clones nested within the ABL1 p.F359V clone, an example of which is shown. The fishplot (e) y axis reflects the inferred cancer cell fraction of the clones at each measured time point, and the shown emergence points of clones are for illustrative purposes. Grey shaded components at the left of the fishplot (dotted and lined) represent historical mutant clones with single (grey dotted) and two (grey dashed) driver mutations from BCR::ABL1, RUNX1 and DNMT3A: the ordering of these events is unknown. The tree plot (f) shows the same tree solution as e, with annotation of autosomal SNV burden for respective subclones. Dashed lines represent a possible branching structure. Boxes are labelled with respective clonal fractions for blast phase sample PD60243d.
