Changes in an epigenetic mechanism that turns expression of genes on and off may be as important as genetic alterations in causing pediatric acute lymphoblastic leukemia (ALL), according to a study led by scientists at St. Jude Children\u2019s Research Hospital.
\nThe results suggest the mechanism called cytosine methylation plays a previously under-appreciated role in the development of leukaemia. Cytosine methylation involves adding or removing methyl groups to cytosine, which is a building block of DNA.
\nThe study is the most comprehensive effort yet to identify and understand genetic and epigenetic factors that work together to cause ALL, the most common childhood cancer. ALL is a cancer of white blood cells known as lymphocytes. Scientists at St. Jude and Weill Cornell Medical College collaborated on the project.
\nResearchers used a variety of techniques to examine hundreds of thousands of methylation sites across the genome in normal and leukemic lymphocytes, including samples from more than 160 children with ALL. Investigators found that known ALL subgroups, which are defined by chromosomal alterations, have unique methylation profiles. Those profiles correlated with different patterns of gene expression.
\n‘It is well known that different leukaemia subgroups have distinct patterns of gene expression that are important in the development of leukaemia,’ said Charles Mullighan, MBBS (Hons), MSc, M.D., an associate member of the St. Jude Department of Pathology. Mullighan and Ari Melnick, M.D., Gebroe Professor Hematology\/Oncology at Weill Cornell Medical College, are the study\u2019s co-corresponding authors.
\n‘We have assumed that the underlying genetic changes are important determinants of those gene expression profiles. We now know that changes in methylation state also have key roles in influencing gene expression,’ Mullighan said.
\nThe study used tissue samples from 137 St. Jude patients with B-cell leukaemia and 30 children with T-cell leukaemia. The patients represented all major ALL subgroups.
\n‘The data show that aberrant epigenetic gene programming can now be considered a hallmark of acute lymphoblastic leukaemia, occurring in all patients regardless of the presence of genetic mutations,’ Melnick said. ‘This offers the opportunity for development of epigenetic targeted therapies for patients with ALL that could be broadly applicable to many patients.’
\nFor comparison, researchers also checked B and T cells from 27 healthy children. Investigators found that leukaemia cells shared a core group of abnormally methylated genes. The genes included ones involved in regulating the cell division and proliferation. ‘This remains to be tested, but the findings suggest that alterations in methylation are an important early step in the development of leukaemia,’ Mullighan said.
\nThe research provides further evidence that genetic and epigenetic events are both important in establishing different subgroups of ALL. For this study, researchers conducted genome-wide sampling of methylation, gene expression and DNA structural abnormalities, including the gain or loss of DNA. Shann-Ching Chen, Ph.D., St. Jude Pathology, developed many of the methods used to integrate and analyse the results. Chen and Maria Figueroa, now of the University of Michigan and formerly of Cornell, are the study\u2019s co-first authors.
\nThe study also found that more than one-third of 71 genes targeted by genetic alterations are also abnormally methylated in ALL. The methylation changes involved known tumor suppressor or oncogenes genes including CDKN2A, CDKN2B, PTEN and KRAS. ‘The findings suggest these genes are inactivated or deregulated more frequently than suggested by simply analysing structural changes in the genome,’ Mullighan said.\nSt. Jude Children\u2019s Research Hospital<\/link>\n","protected":false},"excerpt":{"rendered":"
Changes in an epigenetic mechanism that turns expression of genes on and off may be as important as genetic alterations in causing pediatric acute lymphoblastic leukemia (ALL), according to a study led by scientists at St. Jude Children\u2019s Research Hospital. The results suggest the mechanism called cytosine methylation plays a previously under-appreciated role in the […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"class_list":["post-1844","post","type-post","status-publish","format-standard","hentry","category-e-news"],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1844"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=1844"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1844\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=1844"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=1844"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=1844"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}