Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of bone marrow tumors that have common features including bone marrow failure, abnormal cell morphology, and a high propensity for transformation to acute myeloid leukemia (AML) (Cazzola, 2020, Nimer, 2008). Studies of a vast number of MDS genome sequences have facilitated the comprehensive identification of the gene mutations which are repeatedly found in MDS patients. Among these somatic mutations, BCOR mutations occur in 6.4% of MDS patients (Li et al., 2021) and approximately 4% of normal karyotype AML cases (Grossmann et al., 2011). We thus assume this gene to carry prognostic value.

BCOR is located on chromosome X, in the Xp11.4 locus. It can lead to transcription repression and can act as an interacting corepressor of BCL6 transcription repressor (BCL-6) that promotes BCL-6-mediated transcriptional repression (Huynh et al., 2000). BCOR is a component of the noncanonical polycomb repressive complex 1.1 (PRC1.1) which is involved in a variety of cellular functions including post-translational histone modifications and chromatin compaction (Simon and Kingston, 2013). BCOR is also reported to be involved in embryonic development (Wamstad et al., 2008), cell proliferation, and differentiation (Cao et al., 2016). Furthermore, some studies have identified constitutional inactivating BCOR mutations are responsible for tumor transformation and progression (Kelly et al., 2019, Palomo et al., 2020, Tara et al., 2018). Li et.al have found that BCOR mutations are significantly more frequent in MDS patients with a normal karyotype (8.7%) than in MDS patients with an abnormal karyotype (4.2%) (p=0.040) (Li et al., 2021). Further experiments found that patients with BCOR mutations have a higher proportion of primitive bone marrow cells and a higher risk of leukemic transformation, suggesting that BCOR mutations have an important role in MDS progression. Despite these studies, the clear-cut mechanism linking BCOR mutations with MDS progression and conversion to AML requires further investigations. Li et.al first identified the p.P483L hotspot mutation in exon 4 in normal chromosome MDS patients (23.26%) (Li et al., 2021). Therefore, we were motivated to focus on the role of BCORP483L mutation in MDS progression.

Autophagy is a conservative mechanism used to maintain homeostasis and is an adaptive response to extracellular and intracellular stress. It degrades misfolded proteins, damaged organelles, and intracellular pathogens (Glick et al., 2010). Autophagy exerts complicated effects on the initiation and progression of cancers. On the one hand, autophagy represents a protective mechanism against the accumulation of damaged organelles and genomic material (Mathew et al., 2009, White, 2012). Studies have shown that the repression of autophagic activity is followed by tumor formation and progression (Cianfanelli et al., 2015, Mortensen et al., 2011, Park et al., 2016, Takamura et al., 2011). The autophagy process is tightly regulated by a group of evolutionarily conserved genes named ATGs (autophagy-related genes). When autophagy-related protein 7 (ATG7) or autophagy-related protein 5 (ATG5) was knocked down, nude mice injected with FoxO1(DB)-transfected H1299 cells showed tumor development (Zhao et al., 2010). On the other hand, autophagy supplies fuel that is critical for tumor maintenance and progression (White, 2012). Autophagy is necessary for the maintenance of AML-initiating cells and peripheral survival of myeloblasts (Sumitomo et al., 2016). Furthermore, the loss of autophagy enhances the sensitivity of leukemia cells to chemotherapy (Piya et al., 2016, Sumitomo et al., 2016). However, the mechanisms by which autophagy regulates MDS progression and transformation to AML are largely unknown. Great care should be taken in the investigation of these mechanisms to help improve the therapeutic potential of autophagy-centered intervention.

It is widely recognized that acetylation regulation is present throughout the multistep process of autophagy (Narita et al., 2019, Xie et al., 2015). Histone deacetylase 6 (HDAC6), which belongs to class IIb histone deacetylase, has been reported to be involved in autophagy. It is mainly found in the cytoplasm (Bertos et al., 2004) and can deacetylate various non-histone proteins such as alpha-tubulin, cortactin, and mitochondrial Rho GTPase 1. By modulating the acetylation status of these substrates, HDAC6 plays a vital role in various cellular processes, including the modulation of autophagy and tumor progression (Chang et al., 2021, Li et al., 2020, Li et al., 2018, Sharif et al., 2019, You et al., 2019). Previous reports have proposed that BCOR may functionally link HDACs (Cramer et al., 2017, Huynh et al., 2000). Yet, it remains undefined. Therefore, this study has aimed to investigate whether and how BCORP483L mutation and HDAC6 cooperatively affect MDS progression by modulating autophagy.