JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias.

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 Dev

journal_title

Genes & development

authors

Kim SK,Knight DA,Jones LR,Vervoort S,Ng AP,Seymour JF,Bradner JE,Waibel M,Kats L,Johnstone RW

doi

10.1101/gad.307504.117

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

849-864

issue

11-12

eissn

0890-9369

issn

1549-5477

pii

gad.307504.117

journal_volume

32

pub_type

杂志文章
  • Enzymatic regulation of pattern: BMP4 binds CUB domains of Tolloids and inhibits proteinase activity.

    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

    authors: Lee HX,Mendes FA,Plouhinec JL,De Robertis EM

    更新日期:2009-11-01 00:00:00

  • Seeing the forest for the trees: a wide perspective on RNA-directed DNA methylation.

    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

    authors: Zhang H,Zhu JK

    更新日期:2012-08-15 00:00:00

  • Tumor suppression and normal aging in mice with constitutively high p53 activity.

    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

    authors: Mendrysa SM,O'Leary KA,McElwee MK,Michalowski J,Eisenman RN,Powell DA,Perry ME

    更新日期:2006-01-01 00:00:00

  • Stages in the second reaction of pre-mRNA splicing: the final step is ATP independent.

    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

    authors: Horowitz DS,Abelson J

    更新日期:1993-02-01 00:00:00

  • Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.

    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

    authors: Gottlob K,Majewski N,Kennedy S,Kandel E,Robey RB,Hay N

    更新日期:2001-06-01 00:00:00

  • The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing.

    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

    authors: Vourekas A,Zheng K,Fu Q,Maragkakis M,Alexiou P,Ma J,Pillai RS,Mourelatos Z,Wang PJ

    更新日期:2015-03-15 00:00:00

  • Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport.

    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

    authors: Blacque OE,Reardon MJ,Li C,McCarthy J,Mahjoub MR,Ansley SJ,Badano JL,Mah AK,Beales PL,Davidson WS,Johnsen RC,Audeh M,Plasterk RH,Baillie DL,Katsanis N,Quarmby LM,Wicks SR,Leroux MR

    更新日期:2004-07-01 00:00:00

  • Uniform gene expression in embryos is achieved by temporal averaging of transcription noise.

    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

    authors: Stapel LC,Zechner C,Vastenhouw NL

    更新日期:2017-08-15 00:00:00

  • Caught at its own game: regulatory small RNA inactivated by an inducible transcript mimicking its target.

    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

    authors: Figueroa-Bossi N,Valentini M,Malleret L,Fiorini F,Bossi L

    更新日期:2009-09-01 00:00:00

  • A master CLOCK hard at work brings rhythm to the transcriptome.

    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

    authors: Edery I

    更新日期:2011-11-15 00:00:00

  • Structure and mechanism of the RNA polymerase II transcription machinery.

    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

    authors: Schier AC,Taatjes DJ

    更新日期:2020-04-01 00:00:00

  • 3' end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells.

    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

    authors: Davidson L,Muniz L,West S

    更新日期:2014-02-15 00:00:00

  • Functional domains of the yeast transcription/replication factor MCM1.

    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

    authors: Christ C,Tye BK

    更新日期:1991-05-01 00:00:00

  • Mitochondrial Mg(2+) homeostasis is critical for group II intron splicing in vivo.

    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

    authors: Gregan J,Kolisek M,Schweyen RJ

    更新日期:2001-09-01 00:00:00

  • Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly.

    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

    authors: Vogel RO,Janssen RJ,van den Brand MA,Dieteren CE,Verkaart S,Koopman WJ,Willems PH,Pluk W,van den Heuvel LP,Smeitink JA,Nijtmans LG

    更新日期:2007-03-01 00:00:00

  • Xenopus Sprouty2 inhibits FGF-mediated gastrulation movements but does not affect mesoderm induction and patterning.

    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

    authors: Nutt SL,Dingwell KS,Holt CE,Amaya E

    更新日期:2001-05-01 00:00:00

  • RAG-1 mutations that affect the target specificity of V(D)j recombination: a possible direct role of RAG-1 in site recognition.

    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

    authors: Sadofsky MJ,Hesse JE,van Gent DC,Gellert M

    更新日期:1995-09-01 00:00:00

  • Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.

    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

    authors: Fu J,Murphy KA,Zhou M,Li YH,Lam VH,Tabuloc CA,Chiu JC,Liu Y

    更新日期:2016-08-01 00:00:00

  • Normal human chromosomes have long G-rich telomeric overhangs at one end.

    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

    authors: Wright WE,Tesmer VM,Huffman KE,Levene SD,Shay JW

    更新日期:1997-11-01 00:00:00

  • Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1.

    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

    authors: Sabio G,Cavanagh-Kyros J,Barrett T,Jung DY,Ko HJ,Ong H,Morel C,Mora A,Reilly J,Kim JK,Davis RJ

    更新日期:2010-02-01 00:00:00

  • Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural development.

    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

    authors: Baker JC,Beddington RS,Harland RM

    更新日期:1999-12-01 00:00:00

  • Localization of RecA-like recombination proteins on chromosomes of the lily at various meiotic stages.

    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

    authors: Terasawa M,Shinohara A,Hotta Y,Ogawa H,Ogawa T

    更新日期:1995-04-15 00:00:00

  • Specific regulation of Xenopus chromosomal 5S rRNA gene transcription in vivo by histone H1.

    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

    authors: Bouvet P,Dimitrov S,Wolffe AP

    更新日期:1994-05-15 00:00:00

  • Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development.

    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

    authors: Chen F,Zhou Y,Qi YB,Khivansara V,Li H,Chun SY,Kim JK,Fu XD,Jin Y

    更新日期:2015-11-15 00:00:00

  • mRNA 5'-leader trans-splicing in the chordates.

    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

    authors: Vandenberghe AE,Meedel TH,Hastings KE

    更新日期:2001-02-01 00:00:00

  • Phage N4 RNA polymerase II recruitment to DNA by a single-stranded DNA-binding protein.

    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

    authors: Carter RH,Demidenko AA,Hattingh-Willis S,Rothman-Denes LB

    更新日期:2003-09-15 00:00:00

  • Transcription elongation factor hSPT5 stimulates mRNA capping.

    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

    authors: Wen Y,Shatkin AJ

    更新日期:1999-07-15 00:00:00

  • MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity.

    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

    authors: Grunblatt E,Wu N,Zhang H,Liu X,Norton JP,Ohol Y,Leger P,Hiatt JB,Eastwood EC,Thomas R,Ibrahim AH,Jia D,Basom R,Eaton KD,Martins R,Houghton AM,MacPherson D

    更新日期:2020-09-01 00:00:00

  • Molecular insights into plant cell proliferation disturbance by Agrobacterium protein 6b.

    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

    authors: Wang M,Soyano T,Machida S,Yang JY,Jung C,Chua NH,Yuan YA

    更新日期:2011-01-01 00:00:00

  • eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange.

    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

    authors: Pavitt GD,Ramaiah KV,Kimball SR,Hinnebusch AG

    更新日期:1998-02-15 00:00:00