Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations
The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They r...
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| Veröffentlicht in: | American journal of hematology 2019-06, Vol.94 (6), p.650-657 |
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| creator | Leung, Garret M. K. Zhang, Chunxiao Ng, Nelson K. L. Yang, Ning Lam, Stephen S. Y. Au, Chun H. Chan, Tsun L. Ma, Edmond S. K. Tsui, Sze P. Ip, Ho W. So, Jason C. C. Ng, Margaret H. L. Cheng, Kelvin C. K. Wong, Kit F. Siu, Lisa L. P. Yip, Sze F. Lin, Shek Y. Lau, June S. M. Luk, Tsan H. Lee, Harold K. K. Lau, Chi K. Kho, Bonnie Kwong, Yok L. Leung, Anskar Y. H. |
| description | The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P |
| doi_str_mv | 10.1002/ajh.25469 |
| format | Article |
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K. ; Zhang, Chunxiao ; Ng, Nelson K. L. ; Yang, Ning ; Lam, Stephen S. Y. ; Au, Chun H. ; Chan, Tsun L. ; Ma, Edmond S. K. ; Tsui, Sze P. ; Ip, Ho W. ; So, Jason C. C. ; Ng, Margaret H. L. ; Cheng, Kelvin C. K. ; Wong, Kit F. ; Siu, Lisa L. P. ; Yip, Sze F. ; Lin, Shek Y. ; Lau, June S. M. ; Luk, Tsan H. ; Lee, Harold K. K. ; Lau, Chi K. ; Kho, Bonnie ; Kwong, Yok L. ; Leung, Anskar Y. H.</creator><creatorcontrib>Leung, Garret M. K. ; Zhang, Chunxiao ; Ng, Nelson K. L. ; Yang, Ning ; Lam, Stephen S. Y. ; Au, Chun H. ; Chan, Tsun L. ; Ma, Edmond S. K. ; Tsui, Sze P. ; Ip, Ho W. ; So, Jason C. C. ; Ng, Margaret H. L. ; Cheng, Kelvin C. K. ; Wong, Kit F. ; Siu, Lisa L. P. ; Yip, Sze F. ; Lin, Shek Y. ; Lau, June S. M. ; Luk, Tsan H. ; Lee, Harold K. K. ; Lau, Chi K. ; Kho, Bonnie ; Kwong, Yok L. ; Leung, Anskar Y. H.</creatorcontrib><description>The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.</description><identifier>ISSN: 0361-8609</identifier><identifier>EISSN: 1096-8652</identifier><identifier>DOI: 10.1002/ajh.25469</identifier><identifier>PMID: 30900772</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Abnormal Karyotype ; Acute myeloid leukemia ; Adolescent ; Adult ; Antineoplastic Agents - administration & dosage ; Bone marrow ; Chromosome 5 ; Chromosomes, Human - genetics ; Chromosomes, Human - metabolism ; Clinical outcomes ; Clinical trials ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Etoposide ; Female ; Hematology ; Hematopoietic stem cells ; Humans ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Male ; MDM2 protein ; Middle Aged ; Monosomy ; Mutation ; Myeloid leukemia ; Next-generation sequencing ; p53 Protein ; Sensitivity analysis ; Stem cell transplantation ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Young adults</subject><ispartof>American journal of hematology, 2019-06, Vol.94 (6), p.650-657</ispartof><rights>2019 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4199-a0646a92e1a94069f35c9a605c9929fbbb2dadcacc92557a46ebc659e5d5406d3</citedby><cites>FETCH-LOGICAL-c4199-a0646a92e1a94069f35c9a605c9929fbbb2dadcacc92557a46ebc659e5d5406d3</cites><orcidid>0000-0001-9975-8687 ; 0000-0002-2450-7629</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fajh.25469$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fajh.25469$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30900772$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leung, Garret M. K.</creatorcontrib><creatorcontrib>Zhang, Chunxiao</creatorcontrib><creatorcontrib>Ng, Nelson K. L.</creatorcontrib><creatorcontrib>Yang, Ning</creatorcontrib><creatorcontrib>Lam, Stephen S. Y.</creatorcontrib><creatorcontrib>Au, Chun H.</creatorcontrib><creatorcontrib>Chan, Tsun L.</creatorcontrib><creatorcontrib>Ma, Edmond S. K.</creatorcontrib><creatorcontrib>Tsui, Sze P.</creatorcontrib><creatorcontrib>Ip, Ho W.</creatorcontrib><creatorcontrib>So, Jason C. C.</creatorcontrib><creatorcontrib>Ng, Margaret H. L.</creatorcontrib><creatorcontrib>Cheng, Kelvin C. K.</creatorcontrib><creatorcontrib>Wong, Kit F.</creatorcontrib><creatorcontrib>Siu, Lisa L. P.</creatorcontrib><creatorcontrib>Yip, Sze F.</creatorcontrib><creatorcontrib>Lin, Shek Y.</creatorcontrib><creatorcontrib>Lau, June S. M.</creatorcontrib><creatorcontrib>Luk, Tsan H.</creatorcontrib><creatorcontrib>Lee, Harold K. K.</creatorcontrib><creatorcontrib>Lau, Chi K.</creatorcontrib><creatorcontrib>Kho, Bonnie</creatorcontrib><creatorcontrib>Kwong, Yok L.</creatorcontrib><creatorcontrib>Leung, Anskar Y. H.</creatorcontrib><title>Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations</title><title>American journal of hematology</title><addtitle>Am J Hematol</addtitle><description>The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.</description><subject>Abnormal Karyotype</subject><subject>Acute myeloid leukemia</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Bone marrow</subject><subject>Chromosome 5</subject><subject>Chromosomes, Human - genetics</subject><subject>Chromosomes, Human - metabolism</subject><subject>Clinical outcomes</subject><subject>Clinical trials</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Etoposide</subject><subject>Female</subject><subject>Hematology</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Male</subject><subject>MDM2 protein</subject><subject>Middle Aged</subject><subject>Monosomy</subject><subject>Mutation</subject><subject>Myeloid leukemia</subject><subject>Next-generation sequencing</subject><subject>p53 Protein</subject><subject>Sensitivity analysis</subject><subject>Stem cell transplantation</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Young adults</subject><issn>0361-8609</issn><issn>1096-8652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kctuFDEURC0EIkNgwQ8gS2yIxGRsd9szXkYhEFAkWIS15XbfJp740fgh6G_hZzGZkAUSd-FrycelUhVCLyk5pYSwjd7fnDLeC_kIrSiRYr0TnD1GK9IJ2u5EHqFnOe8JobTfkafoqCOSkO2WrdCvdzYXG0zBvhZdbAw4z2BKqv4tNs4Ga7TDsRYTPWAdRlxuIOkZarEGJ8hzDBkyjhMuy3wHN3J28HPjY4g5-gXf6rTE9tr-m1oA-wVctCN2UG_BW42NTmmx4Ru-_sK7ByP5OXoyaZfhxf0-Rl_fX1yfX66vPn_4eH52tTY9lXKtieiFlgyolj0Rcuq4kVqQdkomp2EY2KhHo42RjPOt7gUMRnAJfOSNH7tj9OagO6f4vUIuyttswDkdINasGJUtT97SbOjrf9B9rCk0d4q1EVtJ-l2jTg6USTHnBJOak_UtBUWJ-tOYao2pu8Ya--pesQ4exgfyb0UN2ByAH9bB8n8ldfbp8iD5Gze-o4c</recordid><startdate>201906</startdate><enddate>201906</enddate><creator>Leung, Garret M. K.</creator><creator>Zhang, Chunxiao</creator><creator>Ng, Nelson K. L.</creator><creator>Yang, Ning</creator><creator>Lam, Stephen S. Y.</creator><creator>Au, Chun H.</creator><creator>Chan, Tsun L.</creator><creator>Ma, Edmond S. K.</creator><creator>Tsui, Sze P.</creator><creator>Ip, Ho W.</creator><creator>So, Jason C. C.</creator><creator>Ng, Margaret H. L.</creator><creator>Cheng, Kelvin C. K.</creator><creator>Wong, Kit F.</creator><creator>Siu, Lisa L. P.</creator><creator>Yip, Sze F.</creator><creator>Lin, Shek Y.</creator><creator>Lau, June S. M.</creator><creator>Luk, Tsan H.</creator><creator>Lee, Harold K. K.</creator><creator>Lau, Chi K.</creator><creator>Kho, Bonnie</creator><creator>Kwong, Yok L.</creator><creator>Leung, Anskar Y. 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K. ; Lau, Chi K. ; Kho, Bonnie ; Kwong, Yok L. ; Leung, Anskar Y. 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K.</creatorcontrib><creatorcontrib>Zhang, Chunxiao</creatorcontrib><creatorcontrib>Ng, Nelson K. L.</creatorcontrib><creatorcontrib>Yang, Ning</creatorcontrib><creatorcontrib>Lam, Stephen S. Y.</creatorcontrib><creatorcontrib>Au, Chun H.</creatorcontrib><creatorcontrib>Chan, Tsun L.</creatorcontrib><creatorcontrib>Ma, Edmond S. K.</creatorcontrib><creatorcontrib>Tsui, Sze P.</creatorcontrib><creatorcontrib>Ip, Ho W.</creatorcontrib><creatorcontrib>So, Jason C. C.</creatorcontrib><creatorcontrib>Ng, Margaret H. L.</creatorcontrib><creatorcontrib>Cheng, Kelvin C. K.</creatorcontrib><creatorcontrib>Wong, Kit F.</creatorcontrib><creatorcontrib>Siu, Lisa L. P.</creatorcontrib><creatorcontrib>Yip, Sze F.</creatorcontrib><creatorcontrib>Lin, Shek Y.</creatorcontrib><creatorcontrib>Lau, June S. M.</creatorcontrib><creatorcontrib>Luk, Tsan H.</creatorcontrib><creatorcontrib>Lee, Harold K. K.</creatorcontrib><creatorcontrib>Lau, Chi K.</creatorcontrib><creatorcontrib>Kho, Bonnie</creatorcontrib><creatorcontrib>Kwong, Yok L.</creatorcontrib><creatorcontrib>Leung, Anskar Y. H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of hematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leung, Garret M. K.</au><au>Zhang, Chunxiao</au><au>Ng, Nelson K. L.</au><au>Yang, Ning</au><au>Lam, Stephen S. Y.</au><au>Au, Chun H.</au><au>Chan, Tsun L.</au><au>Ma, Edmond S. K.</au><au>Tsui, Sze P.</au><au>Ip, Ho W.</au><au>So, Jason C. C.</au><au>Ng, Margaret H. L.</au><au>Cheng, Kelvin C. K.</au><au>Wong, Kit F.</au><au>Siu, Lisa L. P.</au><au>Yip, Sze F.</au><au>Lin, Shek Y.</au><au>Lau, June S. M.</au><au>Luk, Tsan H.</au><au>Lee, Harold K. K.</au><au>Lau, Chi K.</au><au>Kho, Bonnie</au><au>Kwong, Yok L.</au><au>Leung, Anskar Y. H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations</atitle><jtitle>American journal of hematology</jtitle><addtitle>Am J Hematol</addtitle><date>2019-06</date><risdate>2019</risdate><volume>94</volume><issue>6</issue><spage>650</spage><epage>657</epage><pages>650-657</pages><issn>0361-8609</issn><eissn>1096-8652</eissn><abstract>The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>30900772</pmid><doi>10.1002/ajh.25469</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9975-8687</orcidid><orcidid>https://orcid.org/0000-0002-2450-7629</orcidid></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content; EZB-FREE-00999 freely available EZB journals |
| subjects | Abnormal Karyotype Acute myeloid leukemia Adolescent Adult Antineoplastic Agents - administration & dosage Bone marrow Chromosome 5 Chromosomes, Human - genetics Chromosomes, Human - metabolism Clinical outcomes Clinical trials Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Etoposide Female Hematology Hematopoietic stem cells Humans Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Male MDM2 protein Middle Aged Monosomy Mutation Myeloid leukemia Next-generation sequencing p53 Protein Sensitivity analysis Stem cell transplantation Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Young adults |
| title | Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations |
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