Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes

Klug, Christopher A.; Morrison, Sean J.; Masek, Anna; Hahm, Kyungmin; Smale, Stephen T.

doi:10.1073/pnas.95.2.657

Cited by 155 publications

(122 citation statements)

References 38 publications

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“…Previous studies in mice revealed that a master regulator of hematopoiesis, Ikaros, has splice isoforms specific to HSC, progenitors, and progeny cells (26). The mechanism(s) responsible for alternative splicing of GSK3␤ have yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, SNPs were shown to create alternative splice acceptor sites responsible for generating GSK3␤ splice isoforms (18). Alternatively, these transcripts could arise through epigenetic fixation of splice isoforms, mutations in a yet unknown splicing element, or spliceosomal errors (26)(27)(28). Of particular significance to the pathogenesis of CML, enforced expression of BCR-ABL in cord blood progenitors was previously reported to induce increased expression of a number of genes involved in alternative splicing (27).…”

Section: Discussionmentioning

confidence: 99%

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Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation

Abrahamsson

Geron

Gotlib

et al. 2009

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

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228

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Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of ␤-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving ␤-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/␤-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3␤, axin 1, ␤-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3␤ kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3␤ have enhanced ␤-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3␤ reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3␤ in GMP LSC, enabling unphosphorylated ␤-catenin to participate in LSC self-renewal. Missplicing of GSK3␤ represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.blast crisis chronic myeloid leukemia ͉ wnt pathway ͉ xenograft ͉ self-renewal ͉ cancer stem cells

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation

Abrahamsson

Geron

Gotlib

et al. 2009

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

Self Cite

228

204

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“…Generally, Ikaros proteins modulate transcription by recruiting co-repressor complex to the promoters of target genes and/or sequestering these genes to the vicinity of hetero-chromatin (Koipally et al, 1999;Sabbattini et al, 2001;Trinh et al, 2001). Intriguingly, di erent isoforms of Ikaros are di erentially expressed at di erent stages of hematopoiesis (Klug et al, 1998), suggesting that regulated expression of Ikaros isoforms could provide ®ne regulation of the expression of lineage speci®c transcription factors.…”

Section: Ikarosmentioning

confidence: 99%

Hematopoietic cytokines, transcription factors and lineage commitment

2002

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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.

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“…The phosphorylation pattern of IK changes as T cells cycle from G1 to G2/M phase, and modulates DNA-binding affinity (36). IK is thought to act as an activator or repressor of gene expression based on its subnuclear distribution and binding partner(s) in naïve CD4 T cells [86,108] . There are also differences in basal Ikaros isoform expression levels between resting and activated mouse and human T cells.…”

Section: Mechanisms For Transcriptional Regulation By Ikmentioning

confidence: 99%

Vasoactive intestinal peptide signaling axis in human leukemia

Dorsam

Benton²,

Failing³

et al. 2011

WJBC

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The vasoactive intestinal peptide (VIP) signaling axis constitutes a master "communication coordinator" between cells of the nervous and immune systems. To date, VIP and its two main receptors expressed in T lymphocytes, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2, mediate critical cellular functions regulating adaptive immunity, including arresting CD4 T cells in G1 of the cell cycle, protection from apoptosis and a potent chemotactic recruiter of T cells to the mucosa associated lymphoid compartment of the gastrointestinal tissues. Since the discovery of VIP in 1970, followed by the cloning of VPAC1 and VPAC2 in the early 1990s, this signaling axis has been associated with common human cancers, including leukemia. This review highlights the present day knowledge of the VIP ligand and its receptor expression profile in T cell leukemia and cell lines. Also, there will be a discussion describing how the anti-leukemic DNA binding transcription factor, Ikaros, regulates VIP receptor expression in primary human CD4 T lymphocytes and T cell lymphoblastic cell lines (e.g. Hut-78). Lastly, future goals will be mentioned that are expected to uncover the role of how the VIP signaling axis contributes to human leukemogenesis, and to establish whether the VIP receptor signature expressed by leukemic blasts can provide therapeutic and/or diagnostic information.

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Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes

Cited by 155 publications

References 38 publications

Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation

Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation

Hematopoietic cytokines, transcription factors and lineage commitment

Vasoactive intestinal peptide signaling axis in human leukemia

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