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Editorials
Chromosome Y loss and drivers of clonal hematopoiesis in myelodysplastic syndrome
Panagiotis Baliakas1 and Lars A. Forsberg1, 2
1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University and 2The Beijer Laboratory, Uppsala University, Uppsala, Sweden
E-mail: LARS A. FORSBERG - lars.forsberg@igp.uu.se doi:10.3324/haematol.2020.266601
In the current issue of Haematologica, Ouseph et al.1 pres- ent new results on the relation between somatic Y chro- mosome loss and hematologic malignancies. Mosaic loss of chromosome Y (LOY) refers to chromosome Y ane- uploidy acquired during life and it is the most common somatic mutation in human blood cells.2-4 Affected men carry cells without the entire Y chromosome in a mosaic fashion due to its loss from progenitor cells during the life- time. Thus, in a single cell LOY is a binary event causing the absence of almost 2% of the male haploid nuclear genome and when measured in bulk blood samples, it is present as a continuous mosaicism affecting a fraction of cells. In normally aging populations, LOY is detectable in at least 10% of peripheral blood cells in about 5%, 20%, 40% and 60% of men around 50, 60, 70 and 90 years of age, respectively.4-12 Furthermore, longitudinal results from sub- jects without known hematologic malignancy suggest that the frequency of blood cells without the Y chromosome typically increases over time.11 However, profound varia- tion in longitudinal patterns can be observed between indi- viduals, with some subjects recovering from LOY over time.11 Interestingly, longitudinal data presented by Ouseph et al. suggest a general increase in the frequency of LOY within subjects developing myelodysplastic syn- drome (MDS).
Since a paper published in 1963,13 mosaic Y chromo- some loss has been recognized as a frequent event in cells of the hematopoietic system and in blood cells of aging men and it was long viewed as a neutral event. In contrast to that old paradigm, recent epidemiological results sug- gest the opposite, showing that men with LOY in blood have an increased risk of all-cause mortality.5,14 For exam- ple, in a cohort of old men we described that men with LOY in at least 35% of peripheral blood cells at study entry survived on average only half as long as controls dur- ing the follow-up period.5 During the last years, LOY in blood has been linked with an increased risk of a continu- ously growing list of diseases, such as various forms of hematologic and non-hematologic cancer,1,5,7,15-18 Alzheimer disease,6 autoimmune conditions,19,20 cardiovascular dis- eases,14,21 schizophrenia,22 diabetes14 and age-related macu- lar degeneration.10 Although LOY is more common in the elderly, it is detectable in younger subjects4,9 and associa- tions with outcomes such as testicular germ cell tumors17 and age-related macular degeneration10 have been report- ed also in younger men. Of note, epidemiological and clin- ical data suggest that, on average, men with COVID-19 have more severe symptoms and higher rates of death than women with this disease. However, the impact of LOY in males vulnerable to the Sars-Cov-2 virus and other infectious diseases is largely unknown. As further dis- cussed by Ouseph et al.,1 the role of LOY in hematologic
malignancies has been elusive. However, in their study they showed that LOY in at least 75% of metaphases in bone marrow samples from a cohort of clinically defined patients was associated with incident as well as prospec- tive diagnoses of myelodysplastic syndrome (MDS). Furthermore, they also describe new results showing that patients with ≥75% LOY had a high prevalence of somatic mutations in genes linked with myeloid neoplasia (espe- cially MDS) and clonal hematopoiesis of indeterminate potential (CHIP). The authors suggest that a high level of LOY (≥75%) is associated with an MDS-type mutation signature, representing a disease-associated clonal prolifer- ation, and conclude that high-proportion LOY is likely to be a true MDS-associated cytogenetic aberration rather than an incidental finding due to aging. Their study pro- vides molecular proof supporting the current praxis of the majority of diagnostics laboratories when it comes to the interpretation of LOY in patients with a suspicion/diagno- sis of MDS. In particular, when LOY is observed in low number of metaphases (<80%) it is considered more an aging-related phenomenon, not important for the clinical management, while when present in a high number of metaphases it is included in the prognostic algorithm.
In addition to age itself, a number of intrinsic and exter- nal risk factors influence individual risk of being a carrier of blood cells without chromosome Y. Genetic susceptibil- ity to LOY has been reported in several recent genome- wide association studies.4,7,8,23 In the largest to date, vari- ants in 156 genetic loci preferentially found near genes involved in cell-cycle regulation, cell proliferation and genome instability were identified.4 The nature of the risk loci suggests that LOY might primarily be an effect of chromosome mis-segregation during mitosis. Given the genetic component in individual propensity to be affected with LOY during lifetime, it is interesting that men of African ancestry display, on average, a lower frequency of LOY compared with men of European ancestry.14 Other reported risk factors for LOY in blood include smok- ing,7,8,10,14,24 obesity14 and exposure to environmental risk factors such as air pollution25 and polycyclic aromatic hydrocarbons.26 For example, we showed that current smokers have an up to 4-fold increased risk of being affected compared with never smokers, with the increase being dose-dependent, and that smoking cessation is asso- ciated with recovery from LOY.24 The transient effect from smoking has been replicated7 and causality established by Mendelian randomization.8
Still largely unresolved questions include how LOY in blood might be associated with risk of disease in other organs. As illustrated in Figure 1, LOY in the immune cells of blood might represent a new and understudied disease mechanism driven by the accumulation of different types
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