Fig. 7: Effect of inhibiting the BMP pathway on CML-iPSC self-renewal.

a Monitoring the pluripotency level of normal (left panel) and CML (right panel) iPSCs treated with IM, BMP inhibitors or the combination of both (IM = 1 µM, LDN = 1 µM, DOR = 2.5 µM) at 72 h using live APh staining. Pictures were taken by IncuCyte live imaging system. Green fluorescent tag illustrates APh positive cells. Orange fluorescent tag stains all of the colonies. b Comparison of surface area expressing APh in CML-iPSCs vs normal. Untreated sample was used as a comparator. Data are expressed as mean ± standard deviation and were compared using Anova and the unpaired Student’s t-test, ***p < 0.001–0.0001, **p < 0.01–0.001, *p < 0.05–0.01, n = 28 pictures for each arm. c Gene expression analysis shows a marked reduction in the expression of ALPL, NANOG and OCT3/4 in CML samples only. d The expression of early differentiation genes assessed in CML-iPSCs when IM is used in combination with either BMP inhibitor. Data normalised with untreated samples. e Schematic diagram demonstrating the potential role of ID1 in CML pathophysiology. Embryonic morphogenic pathways and their downstream targets play key roles in the pathophysiology of CML, the early response gene ID1 could be an important orchestrator in this process. ID1 upregulation occurs through BCR-ABL-dependent and independent mechanisms. ID1 expression is enhanced through BCR-ABL-mediated STAT5 and SRC activation, with the ID1 promoter having a SRC-responsive element upstream of the translational start site. BMP/SMAD signalling regulates ID1 through BRE in its promoter. Therefore, SRC can co-operate with SMAD to induce ID1 expression. Once expressed, ID1 is known to mediate its effects by downregulating p53 and PTEN transcription, resulting in enhanced AKT phosphorylation and AKT-mediated canonical Wnt signalling. ID1 can also enhance G1-S cell cycle progression and augment Hh and Wnt signalling through suppression of CULLIN3, an ubiquitin ligase which targets CyclinE, GLI2 and DVL2 for degradation. BMP and Wnt pathways also converge to regulate the CDX family of homeobox transcription factors, master regulators of HOX gene expression, important transcription factors involved in CML