title: Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia.
abstract: Deletion of the DNA-binding domain of the transcription factor Ikaros generates dominant-negative isoforms that interfere with its activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemia (B-ALL). Here we found that conditional inactivation of the Ikaros DNA-binding domain in early pre-B cells arrested their differentiation at a stage at which integrin-dependent adhesion to niches augmented signaling via mitogen-activated protein kinases, proliferation and self-renewal and attenuated signaling via the pre-B cell signaling complex (pre-BCR) and the differentiation of pre-B cells. Transplantation of polyclonal Ikaros-mutant pre-B cells resulted in long-latency oligoclonal pre-B-ALL, which demonstrates that loss of Ikaros contributes to multistep B cell leukemogenesis. Our results explain how normal pre-B cells transit from a highly proliferative and stroma-dependent phase to a stroma-independent phase during which differentiation is enabled, and suggest potential therapeutic strategies for Ikaros-mutant B-ALL.
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Ila
authors: I
authors: Joshi
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Toshimi
authors: T
authors: Yoshida
authors: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors: Nilamani
authors: N
authors: Jena
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Xiaoqing
authors: X
authors: Qi
authors: School of Biological Sciences, The University of Hong Kong, Hong Kong.
authors: Jiangwen
authors: J
authors: Zhang
authors: 1] Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA. [2] Present address: Chao Family Comprehensive Cancer Center and Division of Hematology/Oncology, University of California, Irvine, Irvine, California, USA.
authors: Richard A
authors: RA
authors: Van Etten
authors: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Katia
authors: K
authors: Georgopoulos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051740:Ikaros Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor