Loss of <i>Tifab</i>, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor–TRAF6 signaling

Varney, Melinda E.; Niederkorn, Madeline; Konno, Hiroyasu; Matsumoto, Takayuki; Gohda, Jin; Yoshida, Nobuaki; Akiyama, Taishin; Christie, Susanne; Fang, Jing; Miller, David; Jerez, Andrés; Karsan, Aly; Maciejewski, Jaroslaw P.; Meetei, Ruhikanta A.; Inoue, Jun; Starczynowski, Daniel T.

doi:10.1084/jem.20141898

Cited by 93 publications

(107 citation statements)

References 53 publications

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“…However, in the instance of progressive BM failure, this argument is not very compelling, because our data indicate that HSC destruction in miR-146a −/− mice is driven by aberrantly activated T cells; therefore, it is not obvious why Traf6 haploinsufficiency, while having a profound effect on other T cell-dependent defects in miR-146a −/− mice, would have little impact on BM failure. Of note, our conclusion on the role of Traf6 runs contrary to some observations that implicated this adapter molecule in the regulation of HSC homeostasis and the pathophysiology of MDS (10,41,42).…”

Section: Traf6contrasting

confidence: 99%

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Magilnick

Reyes

Wang

et al. 2017

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

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microRNA-146a (miR-146a) has been previously implicated as an essential molecular brake, preventing immune overreaction and malignant transformation by attenuating NF-κB signaling, putatively via repression of the Traf6 and Irak1 genes. The exact contribution of miR-146a–mediated silencing of these genes to the control of immune activation is currently unknown. Therefore, we defined the role of the miR-146a–Traf6 signaling axis in the regulation of immune homeostasis using a genetic epistasis analysis in miR-146a−/− mice. We have uncovered a surprising separation of functions at the level of miR-146a targets. Lowering the Traf6 gene dose and consequent attenuation of NF-κB activation rescued several significant miR-146a−/− phenotypes, such as splenomegaly, aberrant myeloproliferation, and excessive inflammatory responses. In contrast, decreasing Traf6 expression had no effect on the development of the progressive bone marrow failure phenotype, as well as lymphomagenesis in miR-146a−/− mice, indicating that miR-146a controls these biological processes through different molecular mechanisms.

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Section: Traf6contrasting

confidence: 99%

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Magilnick

Reyes

Wang

et al. 2017

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

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“…18,19 This is attributed to haploinsufficiency for critical 5q gene(s), which in cooperation with additional signaling networks, drives malignant transformation and clonal evolution in these disorders. [20][21][22] In keeping with this, treatments that are effective in 5q-deleted myeloid malignancies have been shown to directly target critical haploinsufficient 5q genes and their signaling networks. 20 Based on the latter findings, [20][21][22] we hypothesized that similar 5q gene haploinsufficiency mechanisms are likely to operate in BPDCN and that identification of the relevant 5q target genes might lead to new insight into disease biology and therapy.…”

Section: Introductionmentioning

confidence: 92%

“…[20][21][22] In keeping with this, treatments that are effective in 5q-deleted myeloid malignancies have been shown to directly target critical haploinsufficient 5q genes and their signaling networks. 20 Based on the latter findings, [20][21][22] we hypothesized that similar 5q gene haploinsufficiency mechanisms are likely to operate in BPDCN and that identification of the relevant 5q target genes might lead to new insight into disease biology and therapy. In this setting, we have used molecular cloning coupled with molecular cytogenetics and next-generation sequencing to characterize 5q alterations in BPDCN.…”

Section: Introductionmentioning

confidence: 92%

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Emadali

Hoghoughi

Duley

et al. 2016

Blood

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Key Points• NR3C1 haploinsufficiency is found in patients with a plasmacytoid dendritic cell neoplasm characterized by very poor clinical outcome.• Overexpression of lincRNA3q is a consistent feature of malignant cells in these patients and can be abrogated by BET protein inhibition.Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P 5 .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (Blood. 2016;127(24):3040-3053)

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“…7,19 All I-5q had a CDR at band 5q31 ( Figure 1A), encompassing the 1 Mb CDR of high-risk myelodysplastic syndrome/acute myeloid leukemia del(5q). 3,4,20 When we compared I-5q-positive cases with T-5q and T-ALL without del(5q), we found that the expression levels of IRF1, EGR1, CTNNA1, HNRNPAO, TIFAB, and CXXC5, known putative onco-suppressors in in vitro and/or in vivo models [20][21][22][23][24] mapping within the CDR, did not differ between the three groups; while the presence of I-5q was associated with significant down-regulation of NR3C1 and TCF7 genes ( Figure 1B, Online Supplementary Information and Online Supplementary Figures S2 and S3).…”

Section: Interstitial 5q T-cell Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

et al. 2016

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Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor–TRAF6 signaling

Abstract: Varney et al. report that that deletion of the TRAF-interacting protein TIFAB contributes to an MDS-like phenotype in mice by up-regulating TRAF6 and contributing to hematopoietic dysfunction.

Cited by 93 publications

References 53 publications

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

miR-146a – Traf6 regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

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