Abstract:
:Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b Importantly, primary human CBL mutated (CBL mut ) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-of-function mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBL mut myeloid malignancies.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Lv K,Jiang J,Donaghy R,Riling CR,Cheng Y,Chandra V,Rozenova K,An W,Mohapatra BC,Goetz BT,Pillai V,Han X,Todd EA,Jeschke GR,Langdon WY,Kumar S,Hexner EO,Band H,Tong Wdoi
10.1101/gad.297135.117subject
Has Abstractpub_date
2017-05-15 00:00:00pages
1007-1023issue
10eissn
0890-9369issn
1549-5477pii
gad.297135.117journal_volume
31pub_type
杂志文章abstract::Mammalian development requires effective mechanisms to repress genes whose expression would generate inappropriately specified cells. The Polycomb-repressive complex 1 (PRC1) family complexes are central to maintaining this repression. These include a set of canonical PRC1 complexes, each of which contains four core p...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.326488.119
更新日期:2019-07-01 00:00:00
abstract::SpoIIIE is an FtsK-related protein that transports the forespore chromosome across the Bacillus subtilis sporulation septum. We use membrane photobleaching and protoplast assays to demonstrate that SpoIIIE is required for septal membrane fission in the presence of trapped DNA, and that DNA is transported across separa...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1925210
更新日期:2010-06-01 00:00:00
abstract::The nucleosome remodeling factor (NURF) is one of several ISWI-containing protein complexes that catalyze ATP-dependent nucleosome sliding and facilitate transcription of chromatin in vitro. To establish the physiological requirements of NURF, and to distinguish NURF genetically from other ISWI-containing complexes, w...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1032202
更新日期:2002-12-15 00:00:00
abstract::Morphogenesis of the insect kidney, the Malpighian tubules, is controlled in Drosophila by a single large cell, the tip cell. It has been postulated that this cell sends out a mitogenic signal that induces the division of neighboring cells. The signal and the molecules that receive it have remained elusive. We show th...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.12.1781
更新日期:1998-06-15 00:00:00
abstract::Known prions (infectious proteins) are self-propagating amyloids or conformationally altered proteins, but in theory an enzyme necessary for its own activation could also be a prion (or a gene composed of protein). We show that yeast protease B is such a prion, called [beta].[beta] is infectious, reversibly curable, a...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1115803
更新日期:2003-09-01 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::The yeast SAS (Something About Silencing) complex and the histone variant H2A.Z have both previously been linked to an antisilencing function at the subtelomeric regions. SAS is an H4 Lys 16-specific histone acetyltransferase complex. Here we demonstrate that the H4 Lys 16 acetylation by SAS is required for efficient ...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1439206
更新日期:2006-09-15 00:00:00
abstract::A novel system to study early hematopoietic development is described. This report documents the in vitro capacity of murine embryonic stem (ES) cells to differentiate into hematopoietic precursors of most, if not all, of the colony-forming cells found in normal bone marrow. This system is used to correlate the genetic...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.5.728
更新日期:1991-05-01 00:00:00
abstract::RNAi has revolutionized reverse genetics; however, RNAi is not necessarily ubiquitous or constitutive. Lund and colleagues (pp. 1121-1131) show that microRNA (miRNA) effector Argonautes (Agos) are limiting and easily saturated during early Xenopus embryogenesis. Moreover, this stage is devoid of slicing capacity. Supp...
journal_title:Genes & development
pub_type: 评论,杂志文章
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更新日期:2011-06-01 00:00:00
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journal_title:Genes & development
pub_type: 杂志文章
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更新日期:2011-12-15 00:00:00
abstract::During gastrulation of Xenopus embryos the prospective mesoderm is induced initially with domains of dorsal and ventral fate, then further patterned to generate somitic mesoderm by signals from the gastrula organizer. Although Xwnt-8 is expressed in future ventrolateral mesoderm and induces prospective epidermis to di...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.21.2805
更新日期:1996-11-01 00:00:00
abstract::Most eukaryotic mRNAs are translated using a cap-dependent mechanism of translation. However, approximately 10% of mammalian mRNAs initiate translation using a cap-independent mechanism that is not well understood. These mRNAs contain an internal ribosome entry site (IRES) located in the 5' untranslated region. The cr...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1832209
更新日期:2009-12-01 00:00:00
abstract::Several previously known transcription cofactors have been demonstrated in vitro recently to be histone acetyltransferases and deacetyltransferases, suggesting that remodeling of chromatin through histone acetylation plays a fundamental role in gene regulation. Clear evidence has not yet been obtained, however, to dem...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.12.5.640
更新日期:1998-03-01 00:00:00
abstract::Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose depriv...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1985910
更新日期:2010-12-15 00:00:00
abstract::Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, dishevelled (dsh) is required for Wg signaling. We have recently developed a cell culture system for Wg protein ac...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.9.9.1087
更新日期:1995-05-01 00:00:00
abstract::DinI is a recently described negative regulator of the SOS response in Escherichia coli. Here we show that it physically interacts with RecA and prevents the binding of single-stranded DNA to RecA, which is required for the activation of the latter. DinI also displaces ssDNA from a stable RecA-DNA cofilament, thus eli...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.862901
更新日期:2001-02-15 00:00:00
abstract::A new gene, SCH9, was isolated from Saccharomyces cerevisiae by its ability to complement a cdc25ts mutation. Sequence analysis indicates that it encodes a 90,000-dalton protein with a carboxy-terminal domain homologous to yeast and mammalian cAMP-dependent protein kinase catalytic subunits. In addition to suppressing...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.2.5.517
更新日期:1988-05-01 00:00:00
abstract::The Wnt gene family encodes a group of cysteine-rich proteins implicated in intercellular signaling during several stages of vertebrate development. This family includes Wnt-1 and Wnt-3, both discovered as activated oncogenes in mouse mammary tumors. Here we describe the molecular cloning of an additional member of th...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.5.3.381
更新日期:1991-03-01 00:00:00
abstract::Telomerase is a ribonucleoprotein enzyme that adds telomeric repeats to chromosomes, maintaining telomere length and stabilizing chromosome ends. In vitro, telomerase from the ciliate Tetrahymena elongates single-stranded, guanosine-rich DNA primers by adding repeats of the Tetrahymena telomeric sequence, dT2G4. We ha...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.7b.1364
更新日期:1993-07-01 00:00:00
abstract::The amino-terminal histone tails are subject to covalent post-translational modifications such as acetylation, methylation, and phosphorylation. In the histone code hypothesis, these exposed and unstructured histone tails are accessible to a repertoire of regulatory factors that specifically recognize the various modi...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1001502
更新日期:2002-06-15 00:00:00
abstract::Myxococcus xanthus development requires CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of proteins. We show that CsgA and SocA, a protein that can replace CsgA function in vivo, oxidize the 2'-OH glycerol moiety on cardiolipin and phosphatidylglycerol to produce diacylglycerol (DAG), dihydroxyac...
journal_title:Genes & development
pub_type: 杂志文章
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更新日期:2015-09-15 00:00:00
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journal_title:Genes & development
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更新日期:2000-11-01 00:00:00
abstract::During embryonic development, the two Caenorhabditis elegans HSN motor neurons migrate from their birthplace in the tail to positions near the middle of the embryo. Here, we demonstrate that of all cells that undergo long-range migrations, only the HSNs are affected in animals that lack function of the egl-43 gene. We...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.7.11.2097
更新日期:1993-11-01 00:00:00
abstract::The human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases, including cancer. However, its involvement in breast cancer awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold...
journal_title:Genes & development
pub_type: 杂志文章
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更新日期:2015-10-15 00:00:00
abstract::Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Dros...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.1617608
更新日期:2008-01-15 00:00:00
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
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更新日期:2009-11-01 00:00:00
abstract::Antigenic stimulation of the B-cell receptor (BCR) is a central event in the immune response. In contrast, antigen bound to IgG negatively regulates signals from the BCR by cross-linking it to the inhibitory receptor FcgammaRIIB. Here we show that upon cross-linking of BCR or BCR with FcgammaRIIB, the rasGAP-associate...
journal_title:Genes & development
pub_type: 杂志文章
doi:
更新日期:2000-01-01 00:00:00
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journal_title:Genes & development
pub_type: 杂志文章
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更新日期:1996-02-01 00:00:00
abstract::Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mous...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.258483.115
更新日期:2015-03-01 00:00:00
abstract::Alternative splicing factor/splicing factor 2 (ASF/SF2) is the prototype of a family of nuclear proteins highly conserved throughout metazoa, the SR (serine/arginine) proteins. Based largely on in vitro studies, SR proteins have been suggested to play important roles in constitutive and alternative splicing of pre-mRN...
journal_title:Genes & development
pub_type: 杂志文章
doi:10.1101/gad.10.20.2588
更新日期:1996-10-15 00:00:00