FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination

Alkhatib, Alabbas; Werner, Markus; Hug, Eva; Herzog, Sebastian; Eschbach, Cathrin; Faraidun, Hemin; Köhler, Fabian; Wossning, Thomas; Jumaa, Hassan

doi:10.1084/jem.20110216

Cited by 59 publications

(62 citation statements)

References 54 publications

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“…It is tempting to speculate that signaling pathways modulated by miR-17 and miR-19b may cross-talk with each other. Intriguingly, it has been shown that, in pro-B cells, the activation of PI3K is essential in controlling IKZF1 expression and therefore successful VDJ recombination (46). However, under both T H 1 and T H 17 conditions, manipulation of miR-17 did not cause any measurable impact on PTEN expression (Fig.…”

Section: Discussionmentioning

confidence: 89%

miR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-mediated Inflammation

Liu

Jiang

et al. 2014

Journal of Biological Chemistry

129

119

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Background: miRNA is a key component of post-transcriptional network governing the fate of T cells. Results: By targeting PTEN and IKZF4, miR-17-92 cluster promotes T H 17 differentiation and T H 17-related inflammation. Conclusion: miR-19b and miR-17 within the cluster additively promote T H 17 responses through distinct regulatory networks. Significance: Our study provides novel regulatory mechanisms and potential therapeutic candidates against autoimmunity.

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Section: Discussionmentioning

confidence: 89%

miR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-mediated Inflammation

Liu

Jiang

et al. 2014

Journal of Biological Chemistry

129

119

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“…10,12 The immunoglobulin joining chain is involved in immunoglobulin maturation, [31][32][33] whereas IKAROS controls the processing of immature B-cell receptors into immunoglobulins. 34,35 Whether IKZF1 deletions functionally affect this maturation process clearly warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL

Veer

Waanders

Pieters

et al. 2013

Blood

258

243

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Key Points• BCR-ABL1-like signature and IKZF1 deletions are clinically important to identify high-risk acute lymphoblastic patients.Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the cooccurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies. (Blood. 2013;122(15):2622-2629

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“…4 G and H), indicating that Ras inhibits receptor editing via the PI3K pathway. During B-cell development, PI3K has been shown to down-modulate rag transcription by reducing the protein levels of FoxO1, a transcription factor necessary for Rag expression (18,47). Studies in splenic B cells suggest that PI3K signaling impinges on both mRNA and protein levels of FoxO1 (48).…”

Section: Ras Usesmentioning

confidence: 99%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

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

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Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Tolllike receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance.Src | BAFF

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FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination

Abstract: During murine B cell development, PI3 kinase inhibits Ig gene rearrangement by suppressing FoxO1, which mediates Ikaros mRNA splicing; Ikaros is needed for Ig gene recombination.

Cited by 59 publications

References 54 publications

miR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-mediated Inflammation

miR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-mediated Inflammation

Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

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