Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples
In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 poi...
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| Veröffentlicht in: | Leukemia 2006-07, Vol.20 (7), p.1217-1220 |
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| creator | CLOOS, J GOEMANS, B. F CREUTZIG, U SCHUURHUIS, G. J ZWAAN, Ch. M KASPERS, G. J. L HESS, C. J VAN OOSTVEEN, J. W WAISFISZ, Q CORTHALS, S DE LANGE, D BOECKX, N HÄHLEN, K REINHARDT, D |
| description | In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P |
| doi_str_mv | 10.1038/sj.leu.2404246 |
| format | Article |
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F ; CREUTZIG, U ; SCHUURHUIS, G. J ; ZWAAN, Ch. M ; KASPERS, G. J. L ; HESS, C. J ; VAN OOSTVEEN, J. W ; WAISFISZ, Q ; CORTHALS, S ; DE LANGE, D ; BOECKX, N ; HÄHLEN, K ; REINHARDT, D</creator><creatorcontrib>CLOOS, J ; GOEMANS, B. F ; CREUTZIG, U ; SCHUURHUIS, G. J ; ZWAAN, Ch. M ; KASPERS, G. J. L ; HESS, C. J ; VAN OOSTVEEN, J. W ; WAISFISZ, Q ; CORTHALS, S ; DE LANGE, D ; BOECKX, N ; HÄHLEN, K ; REINHARDT, D</creatorcontrib><description>In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/sj.leu.2404246</identifier><identifier>PMID: 16642044</identifier><identifier>CODEN: LEUKED</identifier><language>eng</language><publisher>London: Nature Publishing</publisher><subject>Acute myeloid leukemia ; Adolescent ; Adult ; Biological and medical sciences ; Cell growth ; Female ; Flt3 protein ; fms-Like Tyrosine Kinase 3 - genetics ; Genetic Markers ; Genetic Predisposition to Disease - epidemiology ; Hematologic and hematopoietic diseases ; Hematology ; Humans ; Influence ; Kinases ; Leukemia ; Leukemia, Erythroblastic, Acute - genetics ; Leukemia, Megakaryoblastic, Acute - genetics ; Leukemia, Monocytic, Acute - genetics ; Leukemia, Myeloid, Acute - epidemiology ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myelomonocytic, Acute - genetics ; Leukemia, Promyelocytic, Acute - genetics ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Male ; Medical prognosis ; Medical sciences ; Minimal residual disease ; Mutation ; Neoplasm, Residual - epidemiology ; Neoplasm, Residual - genetics ; Oncology ; Patients ; Pediatrics ; Point Mutation ; Prognosis ; Protein-tyrosine kinase ; Recurrence ; Risk Factors ; Stem cells ; Tandem Repeat Sequences ; Tyrosine</subject><ispartof>Leukemia, 2006-07, Vol.20 (7), p.1217-1220</ispartof><rights>2006 INIST-CNRS</rights><rights>COPYRIGHT 2006 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2006</rights><rights>Nature Publishing Group 2006.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-5651afbca98f8934d8df240f2c6d692cf5b924f786119e4a8c1af0ce5400ae3b3</citedby><cites>FETCH-LOGICAL-c582t-5651afbca98f8934d8df240f2c6d692cf5b924f786119e4a8c1af0ce5400ae3b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17905376$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16642044$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CLOOS, J</creatorcontrib><creatorcontrib>GOEMANS, B. F</creatorcontrib><creatorcontrib>CREUTZIG, U</creatorcontrib><creatorcontrib>SCHUURHUIS, G. J</creatorcontrib><creatorcontrib>ZWAAN, Ch. M</creatorcontrib><creatorcontrib>KASPERS, G. J. L</creatorcontrib><creatorcontrib>HESS, C. J</creatorcontrib><creatorcontrib>VAN OOSTVEEN, J. W</creatorcontrib><creatorcontrib>WAISFISZ, Q</creatorcontrib><creatorcontrib>CORTHALS, S</creatorcontrib><creatorcontrib>DE LANGE, D</creatorcontrib><creatorcontrib>BOECKX, N</creatorcontrib><creatorcontrib>HÄHLEN, K</creatorcontrib><creatorcontrib>REINHARDT, D</creatorcontrib><title>Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples</title><title>Leukemia</title><addtitle>Leukemia</addtitle><description>In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.</description><subject>Acute myeloid leukemia</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Cell growth</subject><subject>Female</subject><subject>Flt3 protein</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>Genetic Markers</subject><subject>Genetic Predisposition to Disease - epidemiology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematology</subject><subject>Humans</subject><subject>Influence</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Erythroblastic, Acute - genetics</subject><subject>Leukemia, Megakaryoblastic, Acute - genetics</subject><subject>Leukemia, Monocytic, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - epidemiology</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myelomonocytic, Acute - genetics</subject><subject>Leukemia, Promyelocytic, Acute - genetics</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical sciences</subject><subject>Minimal residual disease</subject><subject>Mutation</subject><subject>Neoplasm, Residual - epidemiology</subject><subject>Neoplasm, Residual - genetics</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Point Mutation</subject><subject>Prognosis</subject><subject>Protein-tyrosine kinase</subject><subject>Recurrence</subject><subject>Risk Factors</subject><subject>Stem cells</subject><subject>Tandem Repeat Sequences</subject><subject>Tyrosine</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kkFv1DAQhS0EotvClSOKQO0ti-3YjnNcVRSQFnGgnK2JY7deOXGwnUP_Pd4SaQEV-WBr5psZv9FD6A3BW4Ib-SEdtt4sW8owo0w8QxvCWlFzzslztMFStrXoKDtD5ykdMD4mxUt0RoRgFDO2Qep7ht55lx8qmIZqjuFuCik7XbnJ-sVM2lTBVjf726YalwzZhSmVXDWDi2YoL5cd-MfiaDzMqQR3X_dVgnH2Jr1CLyz4ZF6v9wX6cfPx9vpzvf_26cv1bl9rLmmuueAEbK-hk1Z2DRvkYIsmS7UYigBteV9k2FYKQjrDQOqCY204wxhM0zcX6Op336Lg52JSVqNL2ngPkwlLUkISzLgUBXz_D3gIS5zK3xQVjLe47Rgt1Lv_UhRz0Xa0ObW6A29U2VfIEfRxrtoRKXmDO3IcuH2CKmcwo9NhMtaV-F8FV38U3Bvw-T4Fvzyu_snOOoaUorFqjm6E-KAIVkd3qHRQxR1qdUcpeLuqWvrRDCd8tUMBLlcAkgZvI0zapRPXdpg3rWh-ATTBv5w</recordid><startdate>20060701</startdate><enddate>20060701</enddate><creator>CLOOS, J</creator><creator>GOEMANS, B. 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F ; CREUTZIG, U ; SCHUURHUIS, G. J ; ZWAAN, Ch. M ; KASPERS, G. J. L ; HESS, C. J ; VAN OOSTVEEN, J. 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Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical sciences</topic><topic>Minimal residual disease</topic><topic>Mutation</topic><topic>Neoplasm, Residual - epidemiology</topic><topic>Neoplasm, Residual - genetics</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pediatrics</topic><topic>Point Mutation</topic><topic>Prognosis</topic><topic>Protein-tyrosine kinase</topic><topic>Recurrence</topic><topic>Risk Factors</topic><topic>Stem cells</topic><topic>Tandem Repeat Sequences</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CLOOS, J</creatorcontrib><creatorcontrib>GOEMANS, B. F</creatorcontrib><creatorcontrib>CREUTZIG, U</creatorcontrib><creatorcontrib>SCHUURHUIS, G. J</creatorcontrib><creatorcontrib>ZWAAN, Ch. M</creatorcontrib><creatorcontrib>KASPERS, G. J. L</creatorcontrib><creatorcontrib>HESS, C. 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We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.</abstract><cop>London</cop><pub>Nature Publishing</pub><pmid>16642044</pmid><doi>10.1038/sj.leu.2404246</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Acute myeloid leukemia Adolescent Adult Biological and medical sciences Cell growth Female Flt3 protein fms-Like Tyrosine Kinase 3 - genetics Genetic Markers Genetic Predisposition to Disease - epidemiology Hematologic and hematopoietic diseases Hematology Humans Influence Kinases Leukemia Leukemia, Erythroblastic, Acute - genetics Leukemia, Megakaryoblastic, Acute - genetics Leukemia, Monocytic, Acute - genetics Leukemia, Myeloid, Acute - epidemiology Leukemia, Myeloid, Acute - genetics Leukemia, Myelomonocytic, Acute - genetics Leukemia, Promyelocytic, Acute - genetics Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Male Medical prognosis Medical sciences Minimal residual disease Mutation Neoplasm, Residual - epidemiology Neoplasm, Residual - genetics Oncology Patients Pediatrics Point Mutation Prognosis Protein-tyrosine kinase Recurrence Risk Factors Stem cells Tandem Repeat Sequences Tyrosine |
| title | Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples |
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