BACKGROUND: MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. DESIGN AND METHODS: Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. RESULTS: All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001). CONCLUSIONS: Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.
BACKGROUND: MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. DESIGN AND METHODS: Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. RESULTS: All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001). CONCLUSIONS: Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.
Authors: R Pieters; D R Huismans; A H Loonen; K Hählen; A van der Does-van den Berg; E R van Wering; A J Veerman Journal: Lancet Date: 1991-08-17 Impact factor: 79.321
Authors: L Zuurbier; I Homminga; V Calvert; M L te Winkel; J G C A M Buijs-Gladdines; C Kooi; W K Smits; E Sonneveld; A J P Veerman; W A Kamps; M Horstmann; E F Petricoin; R Pieters; J P P Meijerink Journal: Leukemia Date: 2010-09-23 Impact factor: 11.528
Authors: C P Paweletz; L Charboneau; V E Bichsel; N L Simone; T Chen; J W Gillespie; M R Emmert-Buck; M J Roth; E F Petricoin III; L A Liotta Journal: Oncogene Date: 2001-04-12 Impact factor: 9.867
Authors: R Pieters; A H Loonen; D R Huismans; G J Broekema; M W Dirven; M W Heyenbrok; K Hählen; A J Veerman Journal: Blood Date: 1990-12-01 Impact factor: 22.113
Authors: Mary E Ross; Xiaodong Zhou; Guangchun Song; Sheila A Shurtleff; Kevin Girtman; W Kent Williams; Hsi-Che Liu; Rami Mahfouz; Susana C Raimondi; Noel Lenny; Anami Patel; James R Downing Journal: Blood Date: 2003-05-01 Impact factor: 22.113
Authors: Amy Holleman; Meyling H Cheok; Monique L den Boer; Wenjian Yang; Anjo J P Veerman; Karin M Kazemier; Deqing Pei; Cheng Cheng; Ching-Hon Pui; Mary V Relling; Gritta E Janka-Schaub; Rob Pieters; William E Evans Journal: N Engl J Med Date: 2004-08-05 Impact factor: 91.245
Authors: M L Den Boer; D O Harms; R Pieters; K M Kazemier; U Gobel; D Körholz; U Graubner; R J Haas; N Jorch; H J Spaar; G J L Kaspers; W A Kamps; A Van der Does-Van den Berg; E R Van Wering; A J P Veerman; G E Janka-Schaub Journal: J Clin Oncol Date: 2003-09-01 Impact factor: 44.544
Authors: Eng-Juh Yeoh; Mary E Ross; Sheila A Shurtleff; W Kent Williams; Divyen Patel; Rami Mahfouz; Fred G Behm; Susana C Raimondi; Mary V Relling; Anami Patel; Cheng Cheng; Dario Campana; Dawn Wilkins; Xiaodong Zhou; Jinyan Li; Huiqing Liu; Ching-Hon Pui; William E Evans; Clayton Naeve; Limsoon Wong; James R Downing Journal: Cancer Cell Date: 2002-03 Impact factor: 31.743
Authors: M Aricò; M G Valsecchi; B Camitta; M Schrappe; J Chessells; A Baruchel; P Gaynon; L Silverman; G Janka-Schaub; W Kamps; C H Pui; G Masera Journal: N Engl J Med Date: 2000-04-06 Impact factor: 91.245
Authors: Stuart A Rushworth; Megan Y Murray; Lawrence N Barrera; Sally-Anne Heasman; Lyubov Zaitseva; David J Macewan Journal: Am J Cancer Res Date: 2011-11-21 Impact factor: 6.166
Authors: J Krzanowski; J Madzio; A Pastorczak; A Tracz; M Braun; J Tabarkiewicz; A Pluta; W Młynarski; I Zawlik Journal: Oncol Lett Date: 2017-07-18 Impact factor: 2.967
Authors: Violaine Havelange; Parvathi Ranganathan; Susan Geyer; Deedra Nicolet; Xiaomeng Huang; Xueyan Yu; Stefano Volinia; Steven M Kornblau; Michael Andreeff; Carlo M Croce; Guido Marcucci; Clara D Bloomfield; Ramiro Garzon Journal: Blood Date: 2014-03-04 Impact factor: 22.113