Multiple hematopoietic defects and delayed globin switching in Ikaros null mice

López, R.; Schoetz, Stuti; DeAngelis, Kathryn; O’Neill, David; Bank, Arthur

doi:10.1073/pnas.022412699

Cited by 93 publications

(96 citation statements)

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“…[23][24][25]28 Multiple defects were also observed in the myeloid lineages, such as anemia and thrombocythemia. 29 These functional studies in mouse models strongly suggest that decreased Ikaros function is oncogenic. In accordance with the mouse phenotypes, defects in the IKZF1 gene have been observed at high frequencies in human B-and T-cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

Deletions of the transcription factor Ikaros in myeloproliferative neoplasms

et al. 2010

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Transformation to acute leukemia is a major complication of myeloproliferative neoplasms (MPNs), however, the genetic changes leading to transformation remain largely unknown. We screened nine patients with post-MPN leukemia for chromosomal aberrations using microarray karyotyping. Deletions on the short arm of chromosome 7 (del7p) emerged as a recurrent defect. We mapped the common deleted region to the IKZF1 gene, which encodes the transcription factor Ikaros. We further examined the frequency of IKZF1 deletions in a total of 29 post-MPN leukemia and 526 MPN patients without transformation and observed a strong association of IKZF1 deletions with post-MPN leukemia in two independent cohorts. Patients with IKZF1 loss showed complex karyotypes, and del7p was a late event in the genetic evolution of the MPN clone. IKZF1 deletions were observed in both undifferentiated and differentiated myeloid cell types, indicating that IKZF1 loss does not cause differentiation arrest but rather renders progenitors susceptible to transformation, most likely through chromosomal instability. Induced Ikzf1 haploinsufficiency in primary murine progenitors resulted in elevated Stat5 phosphorylation and increased cytokine-dependent growth, suggesting that reduced expression of IKZF1 is sufficient to perturb growth regulation. Thus, IKZF1 loss is an important step in the leukemic transformation of a subpopulation of MPN patients.

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Section: Discussionmentioning

confidence: 99%

Deletions of the transcription factor Ikaros in myeloproliferative neoplasms

et al. 2010

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“…These observations are at least partly in agreement with previous murine studies looking at expression of a partial human ␤-globin locus (32 kb) in Ikaros null mice: these animals showed no defect in the expression of ␥-and ␤-globin in the absence of Ikaros function, a discrepancy with our observations that could be due to interspecies differences or the use of a chimeric human/mouse model; however, they presented a blockade of the switch. 15 This is because Ikaros is normally involved in the PYR complex fixed on the intergenic region. The low EKLF expression-a factor necessary to induce the switch 40 -may also contribute to this defect.…”

Section: Discussionmentioning

confidence: 99%

“…Delayed switching between human ␥-and ␤-globins is also observed in mice with a human ␤-globin minilocus and lacking the Ikaros gene. 15 These studies show that Ikaros is necessary to the formation of the PYR complex, and to switching of murine and human globins. 16,17 The role of Ikaros in erythropoiesis is confirmed by another Ikaros mutation: Ikaros plastic mice have a single amino acid change in the third zinc finger of the N-terminal domain (ENU-induced nucleotide mutation), and die between embryonic day (E) 15.5 and E17.5 with severe anemia 18 ; numbers of erythroid progenitors (erythroid colony-forming units [CFUs-E] and erythroid blastforming units [BFUs-E]), normoblasts, and nonnucleated reticulocytes are reduced, which is due to a failure of normal erythroblast growth and differentiation.…”

Section: Introductionmentioning

confidence: 99%

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The role of Ikaros in human erythroid differentiation

Dijon

Bardin

Murati

et al. 2008

Blood

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Ikaros-a factor that positively or negatively controls gene transcription-is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6)-a known dominant-negative protein that interferes with normal Ikaros activity-in cord blood or apheresis CD34 ؉ cells that were induced to differentiate along the erythroid pathway. Lentivirally induced Ik6-forced expression resulted in increased cell death, decreased cell proliferation, and decreased expression of erythroid-specific genes, including GATA1 and fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid gene expression, including PU1. IntroductionThe transcription factor Ikaros (also known as LyF-1) was first described to interact with Cd3␦ and TdT promoters in murine thymocyte cells. 1,2 Its sequence is highly conserved between mice and humans, [3][4][5] and its expression is high in the developing and adult hematopoietic systems. 1,6 Ikaros proteins are characterized by the presence of 2 Krüppel-like zinc finger domains. The N-terminal domain is involved in DNA binding, 2,7 while the C-terminal domain is required for homo-or heterodimerization with family members and is composed of 2 zinc fingers. 8 The Ikaros gene contains 7 translated exons and encodes 9 isoforms by means of alternative splicing that alters expression of exons 3 to 6. 2,7 In these different proteins, the number of N-terminal zinc fingers varies from 0 to 4; this combination determines DNA binding affinity. At least 3 zinc fingers in this domain are necessary to efficiently bind to DNA. Ik1, Ik2, Ik3, and IKX are considered as functional isoforms. However, Ik4 can only bind DNA on palindromic sequences. 7 Ik5, Ik6, Ik7, and Ik8 are considered dominantnegative (DN) isoforms because of their capacity to bind other isoforms and their inefficiency to bind DNA. 8 Gene-targeting studies evidenced the fundamental role of Ikaros in hematopoiesis, in particular in T and B lymphocytes, natural killer (NK) and dendritic cells, and stem cells. [9][10][11][12] In addition, analysis of Ikaros L/L mice (insertion of the ␤-Gal gene in exon-2 of the Ikaros gene) revealed that Ikaros is expressed at low levels in a majority of Ter-119 ϩ erythroid cells. 10 Other studies of Ikaros DN (deletion of exon 7) and null (deletion of dimerization domain) mice show that Ikaros is important for erythroid differentiation. 13 These mice display a decrease of erythroid precursor numbers, and a drop in hematocrit levels 2 to 3 weeks after birth. In MEL (murine erythroleukemia) cells, Ikaros is associated with the chromatin remodelling PYR complex which binds to an intergenic domain between the ␥-globin and ␤-globin genes, and facilitates the switch be...

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“…Importantly, deletion of this region of the human β-globin locus in transgenic mice delays adult globin switch [76]. Ikaros null mice display only a small increase in the γ/β globin ratio [77]. Mice harboring a point mutation in the third zinc finger of Ikaros (the resulting protein retains its ability to dimerize with isoforms and family members, but is defective in DNA binding) die of anemia in late gestation with a much more severe phenotype [78].…”

Section: Regulation Of γ-Globin Gene Expressionmentioning

confidence: 99%