Defects in Hemopoietic Stem Cell Activity in <i>Ikaros</i> Mutant Mice

Nichogiannopoulou, Aliki; Trevisan, Maryanne; Neben, Steven; Friedrich, Christoph; Georgopoulos, Katia

doi:10.1084/jem.190.9.1201

Cited by 196 publications

(172 citation statements)

References 33 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…5C; for review, see Busslinger 2004;Singh et al 2005). These proteins induce the expression of two essential growth factor receptors, IL-7R␣ and Flt3, in lymphoid progenitors (Nichogiannopoulou et al 1999;DeKoter et al 2002). Once these progenitors are specified, EBF and E2A are required for the initiation of the B-cell expression program.…”

Section: Enforced Expression Of Flt3 On Hematopoietic Cells Impairs Bmentioning

confidence: 99%

Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment

Holmes¹,

Carotta²,

Corcoran³

et al. 2006

Genes Dev.

View full text Add to dashboard Cite

Early B-lymphopoiesis requires the growth-factor receptors, IL-7R and Flt3, and the activity of a number of transcription factors. One factor, Pax5, is required for commitment to the B-cell lineage, although the molecular mechanism by which this occurs is unknown. We demonstrate here that an important function of Pax5 is to repress Flt3 transcription in B-cell progenitors, as Pax5-deficient pro-B cells express abundant Flt3 that is rapidly silenced upon the reintroduction of Pax5, whereas enforced expression of Flt3 in wild-type progenitors significantly impairs B-cell development. These findings demonstrate that the repression of Flt3 by Pax5 is essential for normal B-lymphopoiesis. Hematopoietic stem cells (HSCs) have the dual capacity to self-renew and to give rise to cells of all the blood lineages. Although the identity and diversity of the intermediaries is still not completely understood, it is clear that an early differentiation step from the HSC gives rise to multipotent progenitors that have reduced capacity to self-renew. These progenitors up-regulate the tyrosine kinase receptor Flt3 (also termed flk2 and CD135) (Adolfsson et al. 2001) and efficiently reconstitute the lympho-myeloid but not the erythro-megakaryocytic lineages (Adolfsson et al. 2005). Flt3 is later expressed on a subset of common myeloid progenitors, with dendritic cell (DC) potential (D'Amico and Wu 2003), and common lymphoid progenitors (CLPs) (Sitnicka et al. 2002).Flt3 −/− mice have a severe deficiency in B-cell progenitors, and the mutant HSCs are impaired in their ability to reconstitute lymphoid and myeloid cells in recipient mice (Mackarehtschian et al. 1995). Similarly, Flt3L-deficient mice have significantly reduced numbers of CLPs, B-cell progenitors, DCs, and natural killer (NK) cells (McKenna et al. 2000). Flt3L expressed by bone marrow stroma (Lisovsky et al. 1996), is a weak growth stimulator of Flt3 + CLPs in vitro and synergizes with stem cell factor (SCF) and IL-7 to promote the proliferation of lymphocytes and, most potently, DCs (Ray et al. 1996;Saunders et al. 1996;Veiby et al. 1996). The ability of Flt3 to promote the expression of the IL-7 receptor on CLPs provides a mechanism by which this synergy occurs in early lymphopoiesis (Borge et al. 1999).B-cell specification is controlled by the coordinate activity of a number of transcription factors, including E2A and EBF, which regulate rearrangement of the IgH locus and pre-B-cell receptor expression (for review, see Busslinger 2004;Singh et al. 2005). These factors also induce Pax5, which is essential for the restriction of lymphoid progenitors to the B-cell fate ). In the absence of Pax5, B lymphopoiesis in the bone marrow is blocked at the early pro-B (or pre-BI)-cell stage (Urbanek et al. 1994;Nutt et al. 1997). Analysis of Pax5 −/− pro-B cells has demonstrated that Pax5 plays a dual role in B-cell commitment, activating lineage-specific genes such as CD19 and mb-1 while repressing lineage inappropriate genes such as M-CSR, and Notch1 (Nutt et al. 1998;Souabni ...

show abstract

Section: Enforced Expression Of Flt3 On Hematopoietic Cells Impairs Bmentioning

confidence: 99%

Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment

Holmes¹,

Carotta²,

Corcoran³

et al. 2006

Genes Dev.

View full text Add to dashboard Cite

show abstract

“…Mice lacking all isoforms of Ikaros display decreased expressed of Flk-2 and C-kit on their SKL cells, and show a marked reduction in long-term repopulating units as measured by competitive repopulation, and mice homozygous for Ikaros dominant negative mutation (DNA-binding domain mutated) possess no measurable repopulating activity at all (Nichogiannopoulou et al, 1999). The Ikaros gene products belong to zinc ®nger family of transcription factors.…”

Section: Ikarosmentioning

confidence: 99%

Hematopoietic cytokines, transcription factors and lineage commitment

2002

View full text Add to dashboard Cite

The past two decades have witnessed signi®cant advances in our understanding of the cellular physiology and molecular regulation of hematopoiesis. At the heart of stem cell self-renewal and lineage commitment decisions lies the relative expression levels of lineage-speci®c transcription factors. The expression of these transcription factors in early stem cells may be promiscuous and uctuate, but ultimately comes under the in¯uence of extracellular regulatory signals in the form of hematopoietic cytokines. In this review, we ®rst summarize our current understanding of the phenotypic characterization of hematopoietic stem cells. Next, we describe key known transcription factors which govern stem cell selfrenewal and lineage commitment decisions. Finally, we review data concerning the role of speci®c cytokines in in¯uencing these decisions. From this review, a picture emerges in which stem cell fate decisions are governed by the integrated e ects of intrinsic transcription factors and external signaling pathways initiated by regulatory cytokines.

show abstract

“…In the second step (days 10-13), cells were diluted at 5 ϫ 10 4 or 10 5 cells/mL (for CB or mPB, respectively) and cocultured on an adherent MS5 stromal layer in basal medium supplemented with erythropoietin. In the third step (days [13][14][15][16][17][18][19][20], cells were cultured on MS5 cells in basal medium without cytokine.…”

Section: Lentiviral Vectorsmentioning

confidence: 99%

“…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 between these 2 globins.…”

Section: Introductionmentioning

confidence: 99%

The role of Ikaros in human erythroid differentiation

Dijon

Bardin

Murati

et al. 2008

Blood

View full text Add to dashboard Cite

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...

show abstract

Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice

Cited by 196 publications

References 33 publications

Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment

Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment

Hematopoietic cytokines, transcription factors and lineage commitment

The role of Ikaros in human erythroid differentiation

Contact Info

Product

Resources

About