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V. Krishnan et al.
monoubiquitination (H2AK119ub1),respectively, and in general repress gene expression.68
From a mechanistic standpoint, the most commonly occurring mutations in CML appear to converge in their ability to interact with and function in conjunction with the polycomb group proteins. ASXL1 functions in tran- scriptional repression through its interaction with PRC2 and BAP1.69 BCORL1 is a transcriptional co-repressor that interacts with PCGF1, a core complex of the PRC1.1 com- plex.70 The RUNX1-CBF-b heterodimer mediates tran- scription by binding to RUNX sites, but also represses transcription by interacting and recruiting BMI1 of the PRC1 complex to target sites.71 IKZF1 regulates transcrip- tion by interacting with repressive epigenetic complexes such as HDAC1, HDAC2, CHD3, CHD4, and SWI/SNF complex, and also recruits PRC2 to target gene loci in T cells.72 Thus, while the commonly mutated genes in CML have their own exclusive roles in transcriptional regula- tion, they also share a striking commonality as modula- tors of the PRC. Whether mutated variants of RUNX1,
ASXL1, IKZF1, and BCORL1 drive aberrant PRC recruit- ment and GE in CML remains to be determined.
In this respect, a recent study determined that lym- phoid and myeloid BC transcriptomes are highly congru- ent, and that both undergo PRC-driven epigenetic repro- gramming towards a convergent transcriptomic state.10 PRC-dependent epigenetic reprogramming was attrib- uted to gain- and loss-of-function mutations in members of the PRC1 and PRC2 complexes, respectively. Of these, ongoing BMI1/PRC1 activity contributes to maintaining the BC transcriptome, while EZH2/PRC2-binding was instructional for DNA hypermethylation-dependent gene repression. Importantly, the integrative model proposed by Ko et al. suggests that enrichment for PRC-dependent GE signatures at diagnosis can predict disease transforma- tion and TKI resistance, as highlighted above.10
We also note that dysregulated regulation of PRC has been identified as a key feature of TKI-resistant LSC in CP. EZH2 expression was higher in CML LSC than in nor- mal HSC, and CML LSC have a stronger dependence on
Figure 2. Diagrammatic representation of the ‘seed and soil’ model of chronic myeloid leukemia. The model proposes that both acquired mutations and the cell state of the mutation-acquiring cell contribute to the process of full transformation to blast crisis (BC). A ‘strong’ mutation is defined as being able to confer self- renewal function on a progenitor cell that does not possess inherent self-renewal capacity. A ‘weak’ mutation is unable to confer self-renewal function and can only transform a cell with native self-renewal ability, i.e., a stem cell. For both strong and weak mutations, it is likely that additional genetic and epigenetic events are nec- essary to confer the full suite of features required for BC transformation. The model is also based on the recent finding that BC progenitors which harbor different somatic mutations share a common or core transcriptome enriched for stemness, quiescence, and inflammatory gene expression signatures.20 HSC: hematopoietic stem cell; LSC: leukemia stem cell; MPP: multipotential progenitor; LMPP: lymphoid-primed multipotent progenitor; CMP: common myeloid progenitor; GMP: granu- locyte-macrophage progenitor; TKI-S/R: tyrosine kinase inhibitor-sensitive/resistant cells. Rx: treatment; CP: chronic phase; BC: blast crisis; CML: chronic myeloid leukemia; GE: gene expression.
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haematologica | 2022; 107(2)