Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients
The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine p...
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| Veröffentlicht in: | Annals of hematology 2015-11, Vol.94 (11), p.1829-1837 |
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| creator | Lou, Yinjun Ma, Yafang Sun, Jianai Ye, Xiujin Pan, Hanzhang Wang, Yungui Qian, Wenbin Meng, Haitao Mai, Wenyuan He, JingSong Tong, Hongyan Jin, Jie |
| description | The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (
P
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| doi_str_mv | 10.1007/s00277-015-2477-x |
| format | Article |
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P
< 0.0001), number of relapses (
P
= 0.001), and early relapse (
P
= 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.</description><identifier>ISSN: 0939-5555</identifier><identifier>EISSN: 1432-0584</identifier><identifier>DOI: 10.1007/s00277-015-2477-x</identifier><identifier>PMID: 26294332</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Arsenicals - administration & dosage ; Drug Resistance, Neoplasm - genetics ; Female ; Follow-Up Studies ; Gene Frequency ; Hematology ; Humans ; Leukemia, Promyelocytic, Acute - drug therapy ; Leukemia, Promyelocytic, Acute - epidemiology ; Leukemia, Promyelocytic, Acute - genetics ; Leukemia, Promyelocytic, Acute - pathology ; Longitudinal Studies ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Mutation, Missense ; Oncogene Proteins, Fusion - genetics ; Oncology ; Original Article ; Oxides - administration & dosage ; Recurrence ; Young Adult</subject><ispartof>Annals of hematology, 2015-11, Vol.94 (11), p.1829-1837</ispartof><rights>Springer-Verlag Berlin Heidelberg 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-d354086eb0441ea09fddb56bf5954dcc1a0baf18c0f7117772fa8dfcf7c2b08a3</citedby><cites>FETCH-LOGICAL-c508t-d354086eb0441ea09fddb56bf5954dcc1a0baf18c0f7117772fa8dfcf7c2b08a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00277-015-2477-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00277-015-2477-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26294332$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lou, Yinjun</creatorcontrib><creatorcontrib>Ma, Yafang</creatorcontrib><creatorcontrib>Sun, Jianai</creatorcontrib><creatorcontrib>Ye, Xiujin</creatorcontrib><creatorcontrib>Pan, Hanzhang</creatorcontrib><creatorcontrib>Wang, Yungui</creatorcontrib><creatorcontrib>Qian, Wenbin</creatorcontrib><creatorcontrib>Meng, Haitao</creatorcontrib><creatorcontrib>Mai, Wenyuan</creatorcontrib><creatorcontrib>He, JingSong</creatorcontrib><creatorcontrib>Tong, Hongyan</creatorcontrib><creatorcontrib>Jin, Jie</creatorcontrib><title>Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients</title><title>Annals of hematology</title><addtitle>Ann Hematol</addtitle><addtitle>Ann Hematol</addtitle><description>The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (
P
< 0.0001), number of relapses (
P
= 0.001), and early relapse (
P
= 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Arsenicals - administration & dosage</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene Frequency</subject><subject>Hematology</subject><subject>Humans</subject><subject>Leukemia, Promyelocytic, Acute - drug therapy</subject><subject>Leukemia, Promyelocytic, Acute - epidemiology</subject><subject>Leukemia, Promyelocytic, Acute - genetics</subject><subject>Leukemia, Promyelocytic, Acute - pathology</subject><subject>Longitudinal Studies</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Mutation, Missense</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Oxides - administration & dosage</subject><subject>Recurrence</subject><subject>Young Adult</subject><issn>0939-5555</issn><issn>1432-0584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc2OFCEUhYnROD2jD-DGkLhxgwJF_S07kxk1aaOZ6JpQcFHGKiiBmnS9iY8rZY_GmMgGAt8593IPQs8YfcUobV8nSnnbEspqwkU5HB-gHRMVJ7TuxEO0o33Vk7qsM3Se0i2ljHeCP0ZnvOG9qCq-Qz-u7tS4qOz8F2wjfF_A6xUHiz--P5Cb_c0eT0suz8EnrLzBOngLMW54hORSVl4DzgGrmMA7jXN04egMkEElMDh_hajmFTtf-FHN253SSwY8xzCtMAa95iIbYfkGk1N4LsXA5_QEPbJqTPD0fr9An6-vPl2-JYcPb95d7g9E17TLxFS1oF0DAxWCgaK9NWaom8HWfS2M1kzRQVnWaWpbxtq25VZ1xmrbaj7QTlUX6OXJt_RTfp-ynFzSMI7KQ1iSZC0rMxad6Av64h_0NizRl-5-UbxqGlYVip0oHUNKEayco5tUXCWjcotNnmKTJTa5xSaPRfP83nkZJjB_FL9zKgA_AWneZg_xr9L_df0JMb2m8w</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Lou, Yinjun</creator><creator>Ma, Yafang</creator><creator>Sun, Jianai</creator><creator>Ye, Xiujin</creator><creator>Pan, Hanzhang</creator><creator>Wang, Yungui</creator><creator>Qian, Wenbin</creator><creator>Meng, Haitao</creator><creator>Mai, Wenyuan</creator><creator>He, JingSong</creator><creator>Tong, Hongyan</creator><creator>Jin, Jie</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20151101</creationdate><title>Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients</title><author>Lou, Yinjun ; 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Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (
P
< 0.0001), number of relapses (
P
= 0.001), and early relapse (
P
= 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>26294332</pmid><doi>10.1007/s00277-015-2477-x</doi><tpages>9</tpages></addata></record> |
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| ispartof | Annals of hematology, 2015-11, Vol.94 (11), p.1829-1837 |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Adolescent Adult Aged Antineoplastic Combined Chemotherapy Protocols - therapeutic use Arsenicals - administration & dosage Drug Resistance, Neoplasm - genetics Female Follow-Up Studies Gene Frequency Hematology Humans Leukemia, Promyelocytic, Acute - drug therapy Leukemia, Promyelocytic, Acute - epidemiology Leukemia, Promyelocytic, Acute - genetics Leukemia, Promyelocytic, Acute - pathology Longitudinal Studies Male Medicine Medicine & Public Health Middle Aged Mutation, Missense Oncogene Proteins, Fusion - genetics Oncology Original Article Oxides - administration & dosage Recurrence Young Adult |
| title | Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients |
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