{"id":712,"date":"2019-06-13T11:08:24","date_gmt":"2019-06-13T09:08:24","guid":{"rendered":"https:\/\/www.personalgenomics.it\/en\/?p=712"},"modified":"2022-07-25T11:15:44","modified_gmt":"2022-07-25T09:15:44","slug":"rna-sequencing-reveals-novel-and-rare-fusion-transcripts-in-acute-myeloid-leukemia","status":"publish","type":"post","link":"https:\/\/www.personalgenomics.it\/en\/rna-sequencing-reveals-novel-and-rare-fusion-transcripts-in-acute-myeloid-leukemia\/","title":{"rendered":"RNA Sequencing Reveals Novel and Rare Fusion Transcripts in Acute Myeloid Leukemia"},"content":{"rendered":"<div class=\"fusion-fullwidth fullwidth-box fusion-builder-row-1 fusion-flex-container nonhundred-percent-fullwidth non-hundred-percent-height-scrolling\" style=\"background-color: rgba(255,255,255,0);background-position: center center;background-repeat: no-repeat;border-width: 0px 0px 0px 0px;border-color:#eae9e9;border-style:solid;\" ><div class=\"fusion-builder-row fusion-row fusion-flex-align-items-flex-start\" style=\"max-width:1352px;margin-left: calc(-4% \/ 2 );margin-right: calc(-4% \/ 2 );\"><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-0 fusion_builder_column_1_1 1_1 fusion-flex-column\"><div class=\"fusion-column-wrapper fusion-flex-justify-content-flex-start fusion-content-layout-column\" style=\"background-position:left top;background-repeat:no-repeat;-webkit-background-size:cover;-moz-background-size:cover;-o-background-size:cover;background-size:cover;padding: 0px 0px 0px 0px;\"><style type=\"text\/css\">@media only screen and (max-width:1024px) {.fusion-title.fusion-title-1{margin-top:0px!important; margin-right:0px!important;margin-bottom:15px!important;margin-left:0px!important;}}@media only screen and (max-width:640px) {.fusion-title.fusion-title-1{margin-top:0px!important; margin-right:0px!important;margin-bottom:20px!important; margin-left:0px!important;}}<\/style><div class=\"fusion-title title fusion-title-1 fusion-sep-none fusion-title-text fusion-title-size-three\" style=\"margin-top:0px;margin-right:0px;margin-bottom:15px;margin-left:0px;\"><h3 class=\"title-heading-left\" style=\"margin:0;\">RNA Sequencing Reveals Novel and Rare Fusion Transcripts in Acute Myeloid Leukemia<\/h3><\/div><style type=\"text\/css\">@media only screen and (max-width:1024px) {.fusion-title.fusion-title-2{margin-top:0px!important; margin-right:0px!important;margin-bottom:15px!important;margin-left:0px!important;}}@media only screen and (max-width:640px) {.fusion-title.fusion-title-2{margin-top:0px!important; margin-right:0px!important;margin-bottom:20px!important; margin-left:0px!important;}}<\/style><div class=\"fusion-title title fusion-title-2 fusion-sep-none fusion-title-text fusion-title-size-five\" style=\"margin-top:0px;margin-right:0px;margin-bottom:15px;margin-left:0px;\"><h5 class=\"title-heading-left\" style=\"margin:0;\">Chromosomal rearrangements and fusion genes have a crucial diagnostic, prognostic and therapeutic role in Acute Myeloid Leukemia.<\/h5><\/div><div class=\"fusion-text fusion-text-1\"><p><em><strong>Authors:\u00a0<\/strong>Antonella\u00a0Padella, Giorgia\u00a0Simonetti, Giulia\u00a0Paciello, Anna\u00a0Ferrari, Elisa\u00a0Zago, Carmen\u00a0Baldazzi, Viviana\u00a0Guadagnuolo, Cristina\u00a0Papayannidis, Valentina\u00a0Robustelli, Enrica\u00a0Imbrogno, Nicoletta\u00a0Testoni, Gerardo\u00a0Musuraca, Simona\u00a0Soverini, Massimo\u00a0Delledonne, Ilaria\u00a0Iacobucci, Clelia Tiziana\u00a0Storlazzi, Elisa\u00a0Ficarra\u00a0and\u00a0Giovanni\u00a0Martinelli; Blood2015\u00a0126:3627.<\/em><\/p>\n<\/div><div class=\"fusion-text fusion-text-2\"><p>Acute Myeloid Leukemia (AML) is a highly heterogeneous disease and a complex network of events contribute to its pathogenesis. Chromosomal rearrangements and fusion genes have a crucial diagnostic, prognostic and therapeutic role in AML. A recent RNA sequencing (RNAseq) study on 179 AML revealed that fusion events occur in 45% of patients. However, the leukemogenic potential of these fusions and their prognostic role are still unknown.To identify novel rare gene fusions having a causative role in leukemogenesis and to identify potential targets for personalized therapies, transcriptome profiling was performed on AML cases with rare and poorly described chromosomal translocations.Bone marrow samples were collected from 5 AML patients (#59810, #20 and #84 at diagnosis and #21 and #32 at relapse). RNAseq was performed using the Illumina Hiseq2000 platform. The presence of gene fusions was assessed with deFuse and Chimerascan. Putative fusion genes were prioritized using Pegasus and Oncofuse, in order to select biologically relevant fusions. Chimeras not supported by split reads, occurring in reactive samples, involving not annotated or conjoined genes were removed. The remaining fusions were prioritized according to mapping of partner genes to chromosomes involved in the translocation or to Chimerascan and deFuse concordance.The\u00a0<i>CBF<\/i><i>?<\/i><i>-MYH11<\/i>\u00a0chimera was identified in sample #84, carrying inv(16) aberration, thus confirming the reliability of our analysis.Sample #59810 carried the fusion transcript\u00a0<i>ZEB2-BCL11B<\/i>\u00a0(Driver Score, DS=0.7), which is an in-frame fusion and a rare event in AML associated with t(2;14)(q21;q32). The breakpoint of the fusion mapped in exon 2 of\u00a0<i>ZEB2<\/i> (ENST00000558170) and exon 2 of\u00a0<i>BCL11B<\/i>\u00a0(ENST00000357195). Differently from previous data, this fusion transcript showed 3 splicing isoforms. Type 1 isoform is the full-length chimera and it retains all exons of both genes involved in the translocation. Type 2 isoform was characterized by the junction of exon 2 of\u00a0<i>ZEB2<\/i> and exon 3 of\u00a0<i>BCL11B<\/i>. In type 3 isoform, exon 2 and 3 of\u00a0<i>BCL11B<\/i>\u00a0were removed, resulting in an mRNA composed by exon 2 of\u00a0<i>ZEB2<\/i>\u00a0and exon 4 of\u00a0<i>BCL11B<\/i>. Gene expression profiling showed an upregulation of ZEB2 and BCL11B transcripts in the patient&#8217;s blasts, compared to 53 AML samples with no chromosomal aberrations in the 14q32 region. The same samples showed the\u00a0<i>WT1-CNOT2<\/i>\u00a0chimera, which is a novel out-of-frame fusion (DS= 0.008) related to t(11;12) translocation, identified by cytogenetic analysis.Two new in-frame fusion genes were identified in sample #20:\u00a0<i>CPD-PXT1<\/i> (DS=0.07), which appeared as the reciprocal fusion product of t(6;17) translocation, and\u00a0<i>SAV1-GYPB<\/i>, which remained cryptic at cytogenetic analysis (DS=0.8, alternative splicing events are being investigated).\u00a0<i>SAV1<\/i>\u00a0was downregulated in sample #20 compared to our AML cohort, suggesting the putative loss of a tumour-suppressor gene.Sample #21 carried a t(3;12) translocation and RNAseq identified a novel fusion event between chromosomes 19 and 7, involving the genes\u00a0<i>OAZ<\/i>\u00a0and\u00a0<i>MAFK<\/i>\u00a0(DS=0.9). Finally, no chimeras were confirmed in sample #32 having a t(12;18) translocation.Our data suggest that fusion events are frequent in AML and a number of them cannot be detected by current cytogenetic analyses. Gene fusions cooperate to AML pathogenesis and heterogeneity and we are further investigating the oncogenic potential of the identified translocations. Moreover, the results firmly indicate that different approaches, including G-banding, molecular biology, bioinformatics and statistics, need to be integrated in order to better understand AML pathogenesis and improve patients&#8217; stratification, High-resolution sequencing analysis currently represent the most informative strategy to tailor personalized therapies.Acknowledgements: ELN, AIL, AIRC, progetto Regione-Universit\u00e0 2010-12 (L. Bolondi), Fondazione del Monte di Bologna e Ravenna, FP7 NGS-PTL project. <b>Disclosures<\/b>\u00a0<b>Soverini:<\/b>\u00a0<i>Novartis, Briston-Myers Squibb, ARIAD:<\/i>\u00a0Consultancy.\u00a0<b>Martinelli:<\/b>\u00a0<i>BMS:<\/i>\u00a0Speakers Bureau;\u00a0<i>MSD:<\/i>\u00a0Consultancy;\u00a0<i>Roche:<\/i>\u00a0Consultancy;\u00a0<i>ARIAD:<\/i> Consultancy;\u00a0<i>Novartis:<\/i>\u00a0Speakers Bureau;\u00a0<i>Pfizer:<\/i>\u00a0Consultancy.<\/p>\n<\/div><div ><style>.fusion-body .fusion-button.button-1{border-radius:8px 8px 8px 8px;}<\/style><a class=\"fusion-button button-flat fusion-button-default-size button-default button-1 fusion-button-default-span fusion-button-default-type\" target=\"_blank\" rel=\"noopener noreferrer\" href=\"http:\/\/www.bloodjournal.org\/content\/126\/23\/3627?sso-checked=true\"><span class=\"fusion-button-text\">Read more<\/span><\/a><\/div><\/div><style type=\"text\/css\">.fusion-body .fusion-builder-column-0{width:100% !important;margin-top : 0px;margin-bottom : 0px;}.fusion-builder-column-0 > .fusion-column-wrapper {padding-top : 0px !important;padding-right : 0px !important;margin-right : 1.92%;padding-bottom : 0px !important;padding-left : 0px !important;margin-left : 1.92%;}@media only screen and (max-width:1024px) {.fusion-body .fusion-builder-column-0{width:100% !important;}.fusion-builder-column-0 > .fusion-column-wrapper {margin-right : 1.92%;margin-left : 1.92%;}}@media only screen and (max-width:640px) {.fusion-body .fusion-builder-column-0{width:100% !important;}.fusion-builder-column-0 > .fusion-column-wrapper {margin-right : 1.92%;margin-left : 1.92%;}}<\/style><\/div><\/div><style type=\"text\/css\">.fusion-body .fusion-flex-container.fusion-builder-row-1{ padding-top : 0px;margin-top : 0px;padding-right : 0px;padding-bottom : 0px;margin-bottom : 0px;padding-left : 0px;}<\/style><\/div>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[19],"tags":[],"_links":{"self":[{"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/posts\/712"}],"collection":[{"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/comments?post=712"}],"version-history":[{"count":3,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/posts\/712\/revisions"}],"predecessor-version":[{"id":2122,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/posts\/712\/revisions\/2122"}],"wp:attachment":[{"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/media?parent=712"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/categories?post=712"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.personalgenomics.it\/en\/wp-json\/wp\/v2\/tags?post=712"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}