title: IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+             hematopoietic cells on stromal cells.
abstract: The BCR-ABL1 induces chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic             leukemia (ALL). Recent studies revealed high ratios of loss of the IKZF1 gene             which encodes IKAROS in BCR-ABL1+ ALL and lymphoblastic crisis (LBC) of CML. However,             little is known about the cooperativity between the aberrant IKAROS and BCR-ABL1             in primary human hematopoietic cells. We investigated the effects of expression             of BCR-ABL1 and/or IK6, a natural dominant negative isoform of IKAROS, on proliferation             and differentiation of human CD34+ cord blood cells with or without human bone             marrow-derived stromal cells which support early B cell differentiation. Cell             proliferation was remarkably enhanced by co-expression of BCR-ABL1 and IK6, with             reduced expression of glycophorin A and increased expression of CD41, especially             on stromal cells, compared with expression of BCR-ABL1 alone that resulted in             expansion of erythroid progenitors. Interestingly, p190BCR-ABL1 showed higher             dependency on stromal cells to stimulate cell growth with IK6, than p210BCR-ABL1.             Furthermore, the cooperation was found to depend on direct cell adhesive interaction             of hematopoietic progenitors with stromal cells. These findings suggest that IK6             and BCR-ABL1 synergistically contribute to leukemogenesis in human bone marrow             stromal microenvironment, and may provide a clue to elucidate the mechanisms of             leukemogenesis of Ph+ ALL and CML-LBC.
authors: Department of Microbiology and Molecular Genetics, Mie University                     Graduate School of Medicine, Mie 514-8507, Japan.
authors: Kei
authors: K
authors: Suzuki
authors: Ryoichi
authors: R
authors: Ono
authors: Kohshi
authors: K
authors: Ohishi
authors: Masahiro
authors: M
authors: Masuya
authors: Itaru
authors: I
authors: Kataoka
authors: Bing
authors: B
authors: Liu
authors: Yoshiki
authors: Y
authors: Nakamori
authors: Kazuko
authors: K
authors: Ino
authors: Fumihiko
authors: F
authors: Monma
authors: Hirofumi
authors: H
authors: Hamada
authors: Toshio
authors: T
authors: Kitamura
authors: Naoyuki
authors: N
authors: Katayama
authors: Tetsuya
authors: T
authors: Nosaka
mesh_terms: D018952:Antigens, CD34 / Q000096:biosynthesis*; D002450:Cell Communication / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018920:Coculture Techniques; D005312:Fetal Blood / Q000166:cytology; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; C497239:IKZF1 protein, human; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl