The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells

Ruiz, Anna; Williams, Owen; Brady, Hugh J.M.

doi:10.1002/ijc.23706

Cited by 9 publications

(10 citation statements)

References 22 publications

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“…28 A dominant negative form of Ikaros can immortalize hematopoietic progenitors. 29 Because Angptl3 down-regulates Ikaros in HSCs, we examined the effect of forced expression of Ikaros on HSC activities. Because the efficiency of retroviral infection for fetal liver HSCs/progenitors is significantly higher than that for adult BM cells, we infected fetal liver hematopoietic progenitor Lin Ϫ cells with an MSCV-Ikaros-IRES-GFP retrovirus and transplanted infected GFP ϩ cells into lethally irradiated recipient mice.…”

Section: Angptl3 Down-regulates Ikaros Expression To Enhance Hsc Stemmentioning

confidence: 99%

Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche

Zheng

Huynh

Umikawa

et al. 2011

Blood

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Section: Angptl3 Down-regulates Ikaros Expression To Enhance Hsc Stemmentioning

confidence: 99%

Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche

Zheng

Huynh

Umikawa

et al. 2011

Blood

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“…In early myeloid progenitors, loss of IKZF1 function prolongs cell survival. 16 During erythropoiesis, IKZF1 supports survival of the erythroid lineage, and promotes erythrocyte differentiation at the expense of granulocyte and monocyte differentiation. [17][18][19] In early megakaryopoiesis, IKZF1 represses differentiation by inhibiting genes associated with the NOTCH pathway and later on in differentiation towards megakaryocytes IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia.…”

Section: Introductionmentioning

confidence: 99%

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nby controlling transcriptional regulators, such as GATA1 and RUNX1. 18,20 Although IKZF1 is not required for the initial differentiation towards granulocytes and monocytes, IKZF1 represses differentiation of the basophilic granulocyte lineage and promotes early maturation and survival of the neutrophil granulocyte lineage. 17,21,22 In pediatric AML, monosomy 7 is found in only 4%-5% of patients. The 5-year OS and EFS of pediatric AML patients with monosomy 7 with or without additional cytogenetic or chromosomal aberrations are poor. 23 In adult AML, monosomy 7 is the most frequent single monosomy and has a similar poor 4-year OS as compared to other single autosomal monosomies. 24 Deletions of the short arm of chromosome 7, 7p (del7p) were recurrently found in adult de novo AML and secondary AML developed from myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). [25][26][27] Furthermore, 7p deletions were mapped to the IKZF1 locus and it was shown that loss of IKZF1 is acquired during the progression of MPN to secondairy AML, indicating that loss of IKZF1 contributes to the transformation from MPN to AML. 25 Together, these studies demonstrate that IKZF1 may play a role in myeloid differentiation and that loss of IKZF1 may contribute to myeloid oncogenesis. We, therefore, hypothesized that, in pediatric AML patients with monosomy 7, IKZF1 may be an important player. In this study, we analyzed the frequency of IKZF1 deletions in a pediatric AML cohort, and studied the difference in gene expression of cases with focal IKZF1 deletions, and cases with monosomy 7. Methods Patients' samplesSamples were provided by the Dutch Childhood Oncology Group (DCOG, the Netherlands), the AML-Berliner-FrankfurtMünster Study Group (Germany and Czech Republic), the SaintLouis Hospital (France), and the Royal Hospital for Sick Children (UK). Isolation of genomic DNA and total cellular RNA was performed using Trizol reagent. Each study group provided morphological and cytogenetic classification and clinical data. Institutional review board approval for these studies had been obtained in the participating centers. Detection of deletions and mutations of IKZF1Multiplex ligation-dependent probe amplification (MLPA) was performed using the p335-B1;ALL-IKZF1 kit (MRC Holland, Amsterdam, the Netherlands; data available at http: //www.mlpa.com). The data were analyzed with GeneMarker v. 1.85 (SoftGenetics, State College, Pennsylvania, USA). Data were normalized to reference probes and control samples. A deletion was defined as a peak ratio below 0.75; an amplification was defined as a peak ratio above 1.25.Array comparative genomic hybridization (Array-CGH) was performed using the human genome CGH Microarray 105K (Agilent Technologies, Santa Clara, California, USA) according to the manufacturer's protocol; data were analyzed with Genomic Workbench v. 5.0.14 (Agilent Technologies, Santa Clara, California, USA).Direct sequencing was used to analyze mutations or frameshif...

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“…This confirms that the phenotypes observed in D6-Ikaros are not due to insertional mutagenesis or nonspecific interactions but are dependent on Ikaros' DNA-binding activity. In certain cases, DNA-binding deficient Ikaros proteins have been reported to act as dominant negatives (DNs), through formation of nonfunctional dimers with WT Ikaros family proteins (46)(47)(48). To determine the ability of Ikaros 159A to act as a DN in cortex, we generated double transgenic D6-Ikaros/D6-Ikaros 159A embryos to examine whether Ikaros 159A could rescue the cortical defects caused by overexpression of WT Ikaros.…”

Section: Cortical Progenitor Cell Populations In the Ikaros Transgenimentioning

confidence: 99%

Ikaros promotes early-born neuronal fates in the cerebral cortex

Alsiö

Tarchini

Cayouette

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

109

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During cerebral cortex development, a series of projection neuron types is generated in a fixed temporal order. In Drosophila neuroblasts, the transcription factor hunchback encodes first-born identity within neural lineages. One of its mammalian homologs, Ikaros, was recently reported to play an equivalent role in retinal progenitor cells, raising the question as to whether Ikaros/Hunchback proteins could be general factors regulating the development of early-born fates throughout the nervous system. Ikaros is also expressed in progenitor cells of the mouse cerebral cortex, and this expression is highest during the early stages of neurogenesis and thereafter decreases over time. Transgenic mice with sustained Ikaros expression in cortical progenitor cells and neurons have developmental defects, including displaced progenitor cells within the cortical plate, increased early neural differentiation, and disrupted cortical lamination. Sustained Ikaros expression results in a prolonged period of generation of deep layer neurons into the stages when, normally, only late-born upper layer neurons are generated, as well as a delayed production of late-born neurons. Consequently, more early-born and fewer late-born neurons are present in the cortex of these mice at birth. This phenotype was observed in all parts of the cortex, including those with minimal structural defects, demonstrating that it is not secondary to abnormalities in cortical morphogenesis. These data suggest that Ikaros plays a similar role in regulating early temporal fates in the mammalian cerebral cortex as Ikaros/Hunchback proteins do in the Drosophila nerve cord.

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The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells

Cited by 9 publications

References 22 publications

Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche

Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Ikaros promotes early-born neuronal fates in the cerebral cortex

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