BACKGROUND: Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high-risk biological subsets of childhood ALL [Georgopoulos et al. Cell 1995;83(2):289-299; Mullighan et al. N Engl J Md 2009;360(5):470-480]. PROCEDURES: To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples. To validate downstream targets we performed qPCR on individual patient samples. We also created IKZF1 knockdown B-ALL cell lines with over 50% reduction of Ikaros, mimicking haplosufficient Ikaros deletions, and again performed qPCR to investigate the downstream targets. Finally, to understand the association of Ikaros deletion with a poor prognosis we challenged our IKZF1 knockdown cell lines with chemotherapy and compared responses to IKZF1 wild-type controls. RESULTS: We report a specific gene expression signature of 735 up-regulated and 473 down-regulated genes in IKZF1 deleted primary B-ALL pediatric patient samples. Gene ontology studies revealed an up-regulation of genes associated with cell adhesion, cytoskeletal regulation, and motility in IKZF deleted patient samples. Validated up-regulated target genes in IKZF1 deleted patient samples included CTNND1 and PVRL2 (P = 0.0003 and P = 0.001), and RAB3IP and SPIB (P = 0.005 and P = 0.032) were down-regulated. In further studies in IKZF1 knockdown cell lines, apoptosis assays showed no significant chemoresistance. CONCLUSION: IKZF1 knockdown alone does not impart intrinsic chemotherapy resistance suggesting that the association with a poor prognosis may be due to additional lesions, microenvironmental interactions with the bone marrow niche, or other factors.
BACKGROUND:Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high-risk biological subsets of childhood ALL [Georgopoulos et al. Cell 1995;83(2):289-299; Mullighan et al. N Engl J Md 2009;360(5):470-480]. PROCEDURES: To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples. To validate downstream targets we performed qPCR on individual patient samples. We also created IKZF1 knockdown B-ALL cell lines with over 50% reduction of Ikaros, mimicking haplosufficient Ikaros deletions, and again performed qPCR to investigate the downstream targets. Finally, to understand the association of Ikaros deletion with a poor prognosis we challenged our IKZF1 knockdown cell lines with chemotherapy and compared responses to IKZF1 wild-type controls. RESULTS: We report a specific gene expression signature of 735 up-regulated and 473 down-regulated genes in IKZF1 deleted primary B-ALL pediatric patient samples. Gene ontology studies revealed an up-regulation of genes associated with cell adhesion, cytoskeletal regulation, and motility in IKZF deleted patient samples. Validated up-regulated target genes in IKZF1 deleted patient samples included CTNND1 and PVRL2 (P = 0.0003 and P = 0.001), and RAB3IP and SPIB (P = 0.005 and P = 0.032) were down-regulated. In further studies in IKZF1 knockdown cell lines, apoptosis assays showed no significant chemoresistance. CONCLUSION:IKZF1 knockdown alone does not impart intrinsic chemotherapy resistance suggesting that the association with a poor prognosis may be due to additional lesions, microenvironmental interactions with the bone marrow niche, or other factors.
Authors: Laura E Hogan; Julia A Meyer; Jun Yang; Jinhua Wang; Nicholas Wong; Wenjian Yang; Gregory Condos; Stephen P Hunger; Elizabeth Raetz; Richard Saffery; Mary V Relling; Deepa Bhojwani; Debra J Morrison; William L Carroll Journal: Blood Date: 2011-09-14 Impact factor: 22.113
Authors: A Dupuis; M P Gaub; M Legrain; B Drenou; L Mauvieux; P Lutz; R Herbrecht; S Chan; P Kastner Journal: Leukemia Date: 2012-07-18 Impact factor: 11.528
Authors: R P Kuiper; E Waanders; V H J van der Velden; S V van Reijmersdal; R Venkatachalam; B Scheijen; E Sonneveld; J J M van Dongen; A J P Veerman; F N van Leeuwen; A Geurts van Kessel; P M Hoogerbrugge Journal: Leukemia Date: 2010-05-06 Impact factor: 11.528
Authors: Stephen P Hunger; Xiaomin Lu; Meenakshi Devidas; Bruce M Camitta; Paul S Gaynon; Naomi J Winick; Gregory H Reaman; William L Carroll Journal: J Clin Oncol Date: 2012-03-12 Impact factor: 44.544
Authors: R Marke; J Havinga; J Cloos; M Demkes; G Poelmans; L Yuniati; D van Ingen Schenau; E Sonneveld; E Waanders; R Pieters; R P Kuiper; P M Hoogerbrugge; G J L Kaspers; F N van Leeuwen; B Scheijen Journal: Leukemia Date: 2015-12-29 Impact factor: 11.528
Authors: Michelle Lim; Carolina R Batista; Bruno R de Oliveira; Rachel Creighton; Jacob Ferguson; Kurt Clemmer; Devon Knight; James Iansavitchous; Danish Mahmood; Mariano Avino; Rodney P DeKoter Journal: Mol Cell Biol Date: 2020-08-28 Impact factor: 4.272
Authors: Beatriz Rosales-Rodríguez; Juan Carlos Núñez-Enríquez; Juan Manuel Mejía-Aranguré; Haydeé Rosas-Vargas Journal: Curr Oncol Rep Date: 2020-11-14 Impact factor: 5.075
Authors: Jason H Rogers; Rohit Gupta; Jaime M Reyes; Michael C Gundry; Geraldo Medrano; Anna Guzman; Rogelio Aguilar; Shannon E Conneely; Tidie Song; Cade Johnson; Sean Barnes; Carlo D D Cristobal; Kristen Kurtz; Lorenzo Brunetti; Margaret A Goodell; Rachel E Rau Journal: Blood Adv Date: 2021-10-12
Authors: Elen Oliveira; Elaine S Costa; Juana Ciudad; Giuseppe Gaipa; Łukasz Sedek; Susana Barrena; Tomasz Szczepanski; Chiara Buracchi; Daniela Silvestri; Patrícia F R Siqueira; Fabiana V Mello; Rafael C Torres; Leonardo M R Oliveira; Isabelle V C Fay-Neves; Edwin Sonneveld; Vincent H J van der Velden; Esther Mejstrikova; Josep-Maria Ribera; Valentino Conter; Martin Schrappe; Jacques J M van Dongen; Marcelo G P Land; Alberto Orfao Journal: Cancers (Basel) Date: 2022-06-23 Impact factor: 6.575
Authors: Matthew T Witkowski; Yifang Hu; Kathryn G Roberts; Judith M Boer; Mark D McKenzie; Grace J Liu; Oliver D Le Grice; Cedric S Tremblay; Margherita Ghisi; Tracy A Willson; Martin A Horstmann; Iannis Aifantis; Luisa Cimmino; Seth Frietze; Monique L den Boer; Charles G Mullighan; Gordon K Smyth; Ross A Dickins Journal: J Exp Med Date: 2017-02-11 Impact factor: 14.307
Authors: Austin L Brown; Adam J de Smith; Vincent U Gant; Wenjian Yang; Michael E Scheurer; Kyle M Walsh; Jonathan M Chernus; Noah A Kallsen; Shanna A Peyton; Gareth E Davies; Erik A Ehli; Naomi Winick; Nyla A Heerema; Andrew J Carroll; Michael J Borowitz; Brent L Wood; William L Carroll; Elizabeth A Raetz; Eleanor Feingold; Meenakshi Devidas; Lisa F Barcellos; Helen M Hansen; Libby Morimoto; Alice Y Kang; Ivan Smirnov; Jasmine Healy; Caroline Laverdière; Daniel Sinnett; Jeffrey W Taub; Jillian M Birch; Pamela Thompson; Logan G Spector; Maria S Pombo-de-Oliveira; Andrew T DeWan; Charles G Mullighan; Stephen P Hunger; Ching-Hon Pui; Mignon L Loh; Michael E Zwick; Catherine Metayer; Xiaomei Ma; Beth A Mueller; Stephanie L Sherman; Joseph L Wiemels; Mary V Relling; Jun J Yang; Philip J Lupo; Karen R Rabin Journal: Blood Date: 2019-10-10 Impact factor: 25.476
Authors: Naomi E van der Sligte; Frank J G Scherpen; Arja Ter Elst; Victor Guryev; Frank N van Leeuwen; Eveline S J M de Bont Journal: Exp Hematol Oncol Date: 2015-08-12