Abstract:
:Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Kim SK,Knight DA,Jones LR,Vervoort S,Ng AP,Seymour JF,Bradner JE,Waibel M,Kats L,Johnstone RWdoi
10.1101/gad.307504.117subject
Has Abstractpub_date
2018-06-01 00:00:00pages
849-864issue
11-12eissn
0890-9369issn
1549-5477pii
gad.307504.117journal_volume
32pub_type
杂志文章abstract::In Xenopus embryos, a dorsal-ventral patterning gradient is generated by diffusing Chordin/bone morphogenetic protein (BMP) complexes cleaved by BMP1/Tolloid metalloproteinases in the ventral side. We developed a new BMP1/Tolloid assay using a fluorogenic Chordin peptide substrate and identified an unexpected negative...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1839309
更新日期:2009-11-01 00:00:00
abstract::In this issue of Genes & Development, Wierzbicki and colleagues (pp. 1825-1836) examine the current model of RNA-directed DNA methylation (RdDM) by determining genome-wide distributions of RNA polymerase V (Pol V) occupancy, siRNAs, and DNA methylation. Their data support the key role of base-pairing between Pol V tra...
journal_title:Genes & development
pub_type: 评论,杂志文章
doi:10.1101/gad.200410.112
更新日期:2012-08-15 00:00:00
abstract::The p53 inhibitor murine double-minute gene 2 (Mdm2) is a target for potential cancer therapies, however increased p53 function can be lethal. To directly address whether reduced Mdm2 function can inhibit tumorigenesis without causing detrimental side effects, we exploited a hypomorphic murine allele of mdm2 to compar...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1378506
更新日期:2006-01-01 00:00:00
abstract::We have analyzed pre-mRNA splicing in yeast extracts immunodepleted of the PRP18 protein. We find that while the first step of splicing (cleavage at the 5' splice site, and generation of the exon 1 and lariat intermediates) is unaffected by the absence of PRP18, the second step of splicing (excision of the lariat intr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.2.320
更新日期:1993-02-01 00:00:00
abstract::The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidati...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.889901
更新日期:2001-06-01 00:00:00
abstract::Piwi-piRNA (Piwi-interacting RNA) ribonucleoproteins (piRNPs) enforce retrotransposon silencing, a function critical for preserving the genome integrity of germ cells. The molecular functions of most of the factors that have been genetically implicated in primary piRNA biogenesis are still elusive. Here we show that M...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.254631.114
更新日期:2015-03-15 00:00:00
abstract::Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Here, we show that mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of ci...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1194004
更新日期:2004-07-01 00:00:00
abstract::Transcription is often stochastic. This is seemingly incompatible with the importance of gene expression during development. Here we show that during zebrafish embryogenesis, transcription activation is stochastic due to (1) genes acquiring transcriptional competence at different times in different cells, (2) differen...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.302935.117
更新日期:2017-08-15 00:00:00
abstract::A relevant, yet little recognized feature of antisense regulation is the possibility of switching roles between regulatory and regulated RNAs. Here we show that induction of a Salmonella gene relies on the conversion of a small RNA from effector to regulatory target. The chiP gene (formerly ybfM), identified and chara...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.541609
更新日期:2009-09-01 00:00:00
abstract::In this issue of Genes & Development, Abruzzi et al. (pp. 2374-2386) use chromatin immunoprecipitation (ChIP) tiling array assays (ChIP-chip) to show that physical interactions between circadian (≅24-h) clock machineries and genomes are more widespread than previously thought and provide novel insights into how clocks...
journal_title:Genes & development
pub_type: 评论,杂志文章
doi:10.1101/gad.180984.111
更新日期:2011-11-15 00:00:00
abstract::RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of...
journal_title:Genes & development
pub_type: 杂志文章,评审
doi:10.1101/gad.335679.119
更新日期:2020-04-01 00:00:00
abstract::3' end formation of pre-mRNAs is coupled to their transcription via the C-terminal domain (CTD) of RNA polymerase II (Pol II). Nearly all protein-coding transcripts are matured by cleavage and polyadenylation (CPA), which is frequently misregulated in disease. Understanding how transcription is coordinated with CPA in...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.231274.113
更新日期:2014-02-15 00:00:00
abstract::MCM1 is an essential yeast DNA-binding protein that affects both minichromosome maintenance, in a manner suggesting that it has DNA replication initiation function, and gene expression. It activates alpha-specific genes together with MAT alpha 1, and represses a-specific genes together with MAT alpha 2. Alone, MCM1 ca...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.5.751
更新日期:1991-05-01 00:00:00
abstract::The product of the nuclear MRS2 gene, Mrs2p, is the only candidate splicing factor essential for all group II introns in mitochondria of the yeast Saccharomyces cerevisiae. It has been shown to be an integral protein of the inner mitochondrial membrane, structurally and functionally related to the bacterial CorA Mg(2+...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.201301
更新日期:2001-09-01 00:00:00
abstract::Ecsit is a cytosolic adaptor protein essential for inflammatory response and embryonic development via the Toll-like and BMP (bone morphogenetic protein) signal transduction pathways, respectively. Here, we demonstrate a mitochondrial function for Ecsit (an evolutionary conserved signaling intermediate in Toll pathway...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.408407
更新日期:2007-03-01 00:00:00
abstract::Signal transduction through the FGF receptor is essential for the specification of the vertebrate body plan. Blocking the FGF pathway in early Xenopus embryos inhibits mesoderm induction and results in truncation of the anterior-posterior axis. The Drosophila gene sprouty encodes an antagonist of FGF signaling, which ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.191301
更新日期:2001-05-01 00:00:00
abstract::The RAG-1 protein plays an essential role in V(D)j recombination, but its exact function has not yet been defined. Here we report that a particular mutation in RAG-1 affects recombination by altering the specificity of target sequence usage. Recombination mediated by wild-type RAG-1 is tolerant of a wide range of codi...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.17.2193
更新日期:1995-09-01 00:00:00
abstract::Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.281030.116
更新日期:2016-08-01 00:00:00
abstract::Telomeres protect the ends of linear chromosomes from degradation and abnormal recombination events, and in vertebrates may be important in cellular senescence and cancer. However, very little is known about the structure of human telomeres. In this report we purify telomeres and analyze their termini. We show that fo...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.11.21.2801
更新日期:1997-11-01 00:00:00
abstract::The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mas...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1878510
更新日期:2010-02-01 00:00:00
abstract::We report a new role for Wnt signaling in the vertebrate embryo: the induction of neural tissue from ectoderm. Early expression of mouse wnt8, Xwnt8, beta-catenin, or dominant-negative GSK3 induces the expression of neural-specific markers and inhibits the expression of Bmp4 in Xenopus ectoderm. We show that Wnt8, but...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.23.3149
更新日期:1999-12-01 00:00:00
abstract::The Rad51 and Lim15 proteins of lily, which are homologs of the bacterial RecA protein, were found on chromosomes in various stages of meiotic prophase 1. The presence of both Rad51 and Lim15 proteins as discrete foci on leptotene and zygotene chromosomes and their colocalization suggest that meiotic recombination beg...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.8.925
更新日期:1995-04-15 00:00:00
abstract::The incorporation of histone H1 into chromatin during embryogenesis directs the specific repression of the Xenopus oocyte 5S rRNA genes. An increase in histone H1 content specifically restricts TFIIIA-activated transcription, and a decrease in histone H1 within chromatin facilitates the activation of the oocyte 5S rRN...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.8.10.1147
更新日期:1994-05-15 00:00:00
abstract::Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathw...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.266650.115
更新日期:2015-11-15 00:00:00
abstract::We report the discovery of mRNA 5'-leader trans-splicing (SL trans-splicing) in the chordates. In the ascidian protochordate Ciona intestinalis, the mRNAs of at least seven genes undergo trans-splicing of a 16-nucleotide 5'-leader apparently derived from a 46-nucleotide RNA that shares features with previously charact...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.865401
更新日期:2001-02-01 00:00:00
abstract::Transcription of bacteriophage N4 middle genes is carried out by a phage-coded, heterodimeric RNA polymerase (N4 RNAPII), which belongs to the family of T7-like RNA polymerases. In contrast to phage T7-RNAP, N4 RNAPII displays no activity on double-stranded templates and low activity on single-stranded templates. In v...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1121403
更新日期:2003-09-15 00:00:00
abstract::RNA polymerase II nascent transcripts are capped during pausing before elongation. Here we report that hSPT5, the human homolog of yeast elongation factor SPT5, interacts directly with the capping enzyme. hSPT5 stimulated capping enzyme guanylylation and mRNA capping by severalfold. Although RNA 5'-triphosphatase acti...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.13.14.1774
更新日期:1999-07-15 00:00:00
abstract::Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. I...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.340133.120
更新日期:2020-09-01 00:00:00
abstract::The Agrobacterium Ti plasmid (T-DNA) 6b proteins interact with many different host proteins implicated in plant cell proliferation. Here, we show that Arabidopsis plants overexpressing 6b display microRNA (miRNA) deficiency by directly targeting SERRATE and AGO1 via a specific loop fragment (residues 40-55). In additi...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1985511
更新日期:2011-01-01 00:00:00
abstract::eIF2B is a heteropentameric guanine-nucleotide exchange factor essential for protein synthesis initiation in eukaryotes. Its activity is inhibited in response to starvation or stress by phosphorylation of the alpha subunit of its substrate, translation initiation factor eIF2, resulting in reduced rates of translation ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.4.514
更新日期:1998-02-15 00:00:00