RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia

DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DN...

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Published in:Scientific reports 2020-11, Vol.10 (1), p.20119-20119, Article 20119
Main Authors: Kim, TaeHyung, Moon, Joon Ho, Ahn, Jae-Sook, Ahn, Seo-Yeon, Jung, Sung-Hoon, Yang, Deok-Hwan, Lee, Je-Jung, Shin, Myung-Geun, Choi, Seung Hyun, Lee, Ja-yeon, Tyndel, Marc S., Lee, Hui Young, Kim, Kyoung Ha, Cai, Yu, Lee, Yoo Jin, Sohn, Sang Kyun, Min, Yoo Hong, Cheong, June-Won, Kim, Hyeoung-Joon, Zhang, Zhaolei, Kim, Dennis Dong Hwan
Format: Article
Language:English
Subjects:
631/67/1990
631/67/69
692/53/2422
Adolescent
Adult
Aged
Aged, 80 and over
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factors - genetics
Female
Gene Expression Regulation, Leukemic
Gene Rearrangement
Humanities and Social Sciences
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - mortality
Leukemia, Myeloid, Acute - pathology
Male
Middle Aged
multidisciplinary
Mutation
Myosin Heavy Chains - genetics
Neoplasm, Residual - genetics
Oncogene Proteins, Fusion - genetics
Prognosis
Proof of Concept Study
RUNX1 Translocation Partner 1 Protein - genetics
Science
Science (multidisciplinary)
Sequence Analysis, RNA - methods
Young Adult
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Kim, Hyeoung-Joon
Zhang, Zhaolei
Kim, Dennis Dong Hwan
description DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1 - RUNX1T1 and CBFB - MYH11 at diagnosis and their levels of reduction during remission (P 
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However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1 - RUNX1T1 and CBFB - MYH11 at diagnosis and their levels of reduction during remission (P &lt; 6.3e−05 and P &lt; 2.2e−13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R 2  = 0.74, P &lt; 5.4e−05). A decision tree analysis, based on 3-log reduction of RUNX1 - RUNX1T1 and c KIT -D816 mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P &lt; 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P &lt; 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-76933-2</identifier><identifier>PMID: 33208771</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1990 ; 631/67/69 ; 692/53/2422 ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Core Binding Factor Alpha 2 Subunit - genetics ; Core Binding Factors - genetics ; Female ; Gene Expression Regulation, Leukemic ; Gene Rearrangement ; Humanities and Social Sciences ; Humans ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - mortality ; Leukemia, Myeloid, Acute - pathology ; Male ; Middle Aged ; multidisciplinary ; Mutation ; Myosin Heavy Chains - genetics ; Neoplasm, Residual - genetics ; Oncogene Proteins, Fusion - genetics ; Prognosis ; Proof of Concept Study ; RUNX1 Translocation Partner 1 Protein - genetics ; Science ; Science (multidisciplinary) ; Sequence Analysis, RNA - methods ; Young Adult</subject><ispartof>Scientific reports, 2020-11, Vol.10 (1), p.20119-20119, Article 20119</ispartof><rights>The Author(s) 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-1b6d292e88fda7154eef56325d8b7c9583e90f547efaadc19fdd09023a3a1e3d3</citedby><cites>FETCH-LOGICAL-c446t-1b6d292e88fda7154eef56325d8b7c9583e90f547efaadc19fdd09023a3a1e3d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674449/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674449/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,37012,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33208771$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, TaeHyung</creatorcontrib><creatorcontrib>Moon, Joon Ho</creatorcontrib><creatorcontrib>Ahn, Jae-Sook</creatorcontrib><creatorcontrib>Ahn, Seo-Yeon</creatorcontrib><creatorcontrib>Jung, Sung-Hoon</creatorcontrib><creatorcontrib>Yang, Deok-Hwan</creatorcontrib><creatorcontrib>Lee, Je-Jung</creatorcontrib><creatorcontrib>Shin, Myung-Geun</creatorcontrib><creatorcontrib>Choi, Seung Hyun</creatorcontrib><creatorcontrib>Lee, Ja-yeon</creatorcontrib><creatorcontrib>Tyndel, Marc S.</creatorcontrib><creatorcontrib>Lee, Hui Young</creatorcontrib><creatorcontrib>Kim, Kyoung Ha</creatorcontrib><creatorcontrib>Cai, Yu</creatorcontrib><creatorcontrib>Lee, Yoo Jin</creatorcontrib><creatorcontrib>Sohn, Sang Kyun</creatorcontrib><creatorcontrib>Min, Yoo Hong</creatorcontrib><creatorcontrib>Cheong, June-Won</creatorcontrib><creatorcontrib>Kim, Hyeoung-Joon</creatorcontrib><creatorcontrib>Zhang, Zhaolei</creatorcontrib><creatorcontrib>Kim, Dennis Dong Hwan</creatorcontrib><title>RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. 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On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.</description><subject>631/67/1990</subject><subject>631/67/69</subject><subject>692/53/2422</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Core Binding Factor Alpha 2 Subunit - genetics</subject><subject>Core Binding Factors - genetics</subject><subject>Female</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Gene Rearrangement</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - mortality</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Myosin Heavy Chains - genetics</subject><subject>Neoplasm, Residual - genetics</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Prognosis</subject><subject>Proof of Concept Study</subject><subject>RUNX1 Translocation Partner 1 Protein - genetics</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Sequence Analysis, RNA - methods</subject><subject>Young Adult</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kU1rFTEUhgdRbKn9Ay4kSzej-ZyZbIRS_CgUBdF1OJOcuaZmkppkCl34383traVuzCYh5znvCXm67iWjbxgV09simdJTTzntx0EL0fMn3TGnUvVccP700fmoOy3liraluJZMP--OhOB0Gkd23P3--vmMFPy1YbQ-7ggUApFAqJgjVH-DpKYUyJIycVjR1j20IpQtwxyQZCzebRCI86XdIvGR2JSxn310e3YBW1sz2K0iWW8xJO9IwO0nrh5edM8WCAVP7_eT7vuH99_OP_WXXz5enJ9d9lbKofZsHhzXHKdpcTAyJREXNQiu3DSPVqtJoKaLkiMuAM4yvThHNeUCBDAUTpx07w6519u8orMYa4ZgrrNfId-aBN78W4n-h9mlGzMOo5RSt4DX9wE5tb8q1ay-WAwBIqatGC4HLpkYlWwoP6A2p1IyLg9jGDV7deagzjR15k6d4a3p1eMHPrT8FdUAcQBKK8UdZnOVtqYolP_F_gFdragY</recordid><startdate>20201118</startdate><enddate>20201118</enddate><creator>Kim, TaeHyung</creator><creator>Moon, Joon Ho</creator><creator>Ahn, Jae-Sook</creator><creator>Ahn, Seo-Yeon</creator><creator>Jung, Sung-Hoon</creator><creator>Yang, Deok-Hwan</creator><creator>Lee, Je-Jung</creator><creator>Shin, Myung-Geun</creator><creator>Choi, Seung Hyun</creator><creator>Lee, Ja-yeon</creator><creator>Tyndel, Marc S.</creator><creator>Lee, Hui Young</creator><creator>Kim, Kyoung Ha</creator><creator>Cai, Yu</creator><creator>Lee, Yoo Jin</creator><creator>Sohn, Sang Kyun</creator><creator>Min, Yoo Hong</creator><creator>Cheong, June-Won</creator><creator>Kim, Hyeoung-Joon</creator><creator>Zhang, Zhaolei</creator><creator>Kim, Dennis Dong Hwan</creator><general>Nature Publishing Group UK</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20201118</creationdate><title>RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia</title><author>Kim, TaeHyung ; Moon, Joon Ho ; Ahn, Jae-Sook ; Ahn, Seo-Yeon ; Jung, Sung-Hoon ; Yang, Deok-Hwan ; Lee, Je-Jung ; Shin, Myung-Geun ; Choi, Seung Hyun ; Lee, Ja-yeon ; Tyndel, Marc S. ; Lee, Hui Young ; Kim, Kyoung Ha ; Cai, Yu ; Lee, Yoo Jin ; Sohn, Sang Kyun ; Min, Yoo Hong ; Cheong, June-Won ; Kim, Hyeoung-Joon ; Zhang, Zhaolei ; Kim, Dennis Dong Hwan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-1b6d292e88fda7154eef56325d8b7c9583e90f547efaadc19fdd09023a3a1e3d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/67/1990</topic><topic>631/67/69</topic><topic>692/53/2422</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Core Binding Factor Alpha 2 Subunit - genetics</topic><topic>Core Binding Factors - genetics</topic><topic>Female</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Gene Rearrangement</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - mortality</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Myosin Heavy Chains - genetics</topic><topic>Neoplasm, Residual - genetics</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Prognosis</topic><topic>Proof of Concept Study</topic><topic>RUNX1 Translocation Partner 1 Protein - genetics</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Sequence Analysis, RNA - methods</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, TaeHyung</creatorcontrib><creatorcontrib>Moon, Joon Ho</creatorcontrib><creatorcontrib>Ahn, Jae-Sook</creatorcontrib><creatorcontrib>Ahn, Seo-Yeon</creatorcontrib><creatorcontrib>Jung, Sung-Hoon</creatorcontrib><creatorcontrib>Yang, Deok-Hwan</creatorcontrib><creatorcontrib>Lee, Je-Jung</creatorcontrib><creatorcontrib>Shin, Myung-Geun</creatorcontrib><creatorcontrib>Choi, Seung Hyun</creatorcontrib><creatorcontrib>Lee, Ja-yeon</creatorcontrib><creatorcontrib>Tyndel, Marc S.</creatorcontrib><creatorcontrib>Lee, Hui Young</creatorcontrib><creatorcontrib>Kim, Kyoung Ha</creatorcontrib><creatorcontrib>Cai, Yu</creatorcontrib><creatorcontrib>Lee, Yoo Jin</creatorcontrib><creatorcontrib>Sohn, Sang Kyun</creatorcontrib><creatorcontrib>Min, Yoo Hong</creatorcontrib><creatorcontrib>Cheong, June-Won</creatorcontrib><creatorcontrib>Kim, Hyeoung-Joon</creatorcontrib><creatorcontrib>Zhang, Zhaolei</creatorcontrib><creatorcontrib>Kim, Dennis Dong Hwan</creatorcontrib><collection>Springer Nature Open Access Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, TaeHyung</au><au>Moon, Joon Ho</au><au>Ahn, Jae-Sook</au><au>Ahn, Seo-Yeon</au><au>Jung, Sung-Hoon</au><au>Yang, Deok-Hwan</au><au>Lee, Je-Jung</au><au>Shin, Myung-Geun</au><au>Choi, Seung Hyun</au><au>Lee, Ja-yeon</au><au>Tyndel, Marc S.</au><au>Lee, Hui Young</au><au>Kim, Kyoung Ha</au><au>Cai, Yu</au><au>Lee, Yoo Jin</au><au>Sohn, Sang Kyun</au><au>Min, Yoo Hong</au><au>Cheong, June-Won</au><au>Kim, Hyeoung-Joon</au><au>Zhang, Zhaolei</au><au>Kim, Dennis Dong Hwan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-11-18</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>20119</spage><epage>20119</epage><pages>20119-20119</pages><artnum>20119</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1 - RUNX1T1 and CBFB - MYH11 at diagnosis and their levels of reduction during remission (P &lt; 6.3e−05 and P &lt; 2.2e−13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R 2  = 0.74, P &lt; 5.4e−05). A decision tree analysis, based on 3-log reduction of RUNX1 - RUNX1T1 and c KIT -D816 mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P &lt; 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P &lt; 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33208771</pmid><doi>10.1038/s41598-020-76933-2</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects 631/67/1990
631/67/69
692/53/2422
Adolescent
Adult
Aged
Aged, 80 and over
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factors - genetics
Female
Gene Expression Regulation, Leukemic
Gene Rearrangement
Humanities and Social Sciences
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - mortality
Leukemia, Myeloid, Acute - pathology
Male
Middle Aged
multidisciplinary
Mutation
Myosin Heavy Chains - genetics
Neoplasm, Residual - genetics
Oncogene Proteins, Fusion - genetics
Prognosis
Proof of Concept Study
RUNX1 Translocation Partner 1 Protein - genetics
Science
Science (multidisciplinary)
Sequence Analysis, RNA - methods
Young Adult
title RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia
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