MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia.

Abstract:

:Loss of miR-15/16 is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of BCL2, which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by miR-15/16, which may target other drivers in CLL. We found that miR-15/16 targets ROR1, which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible miR-15/16 Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding miR-15/16 (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of miR-15/16 may promote overexpression of ROR1, in addition to BCL2 ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.

authors

Rassenti LZ,Balatti V,Ghia EM,Palamarchuk A,Tomasello L,Fadda P,Pekarsky Y,Widhopf GF 2nd,Kipps TJ,Croce CM

doi

10.1073/pnas.1708264114

subject

Has Abstract

pub_date

2017-10-03 00:00:00

pages

10731-10736

issue

40

eissn

0027-8424

issn

1091-6490

pii

1708264114

journal_volume

114

pub_type

杂志文章
  • Negative cooperativity in regulatory enzymes.

    abstract::Negative cooperativity has been observed in CTP synthetase, an allosteric enzyme which contains a regulatory site. Thus, the same enzyme exhibits negative cooperativity for GTP (an effector) and glutamine (a substrate) and positive cooperativity for ATP and UTP (both substrates). In the process of the delineation of t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.62.4.1121

    authors: Levitzki A,Koshland DE Jr

    更新日期:1969-04-01 00:00:00

  • CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation.

    abstract::Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1701428114

    authors: Zeissig S,Peuker K,Iyer S,Gensollen T,Dougan SK,Olszak T,Kaser A,Blumberg RS

    更新日期:2017-09-26 00:00:00

  • Peptide and nucleotide sequences of rat CD4 (W3/25) antigen: evidence for derivation from a structure with four immunoglobulin-related domains.

    abstract::The rat W3/25 antigen was the first marker antigen of helper T lymphocytes to be identified. Subsequently, the human OKT4 antigen (now called CD4) was described, and cell distribution and functional data suggested that W3/25 and OKT4 antigens were homologous. This is now confirmed by the matching of peptide sequences ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.6.1649

    authors: Clark SJ,Jefferies WA,Barclay AN,Gagnon J,Williams AF

    更新日期:1987-03-01 00:00:00

  • Ligand-directed retroviral targeting of human breast cancer cells.

    abstract::We explored the feasibility of designing retroviral vectors that can target human breast cancer cells with characteristic receptors via ligand-receptor interaction. The ecotropic Moloney murine leukemia virus envelope was modified by insertion of sequences encoding human heregulin. Ecotropic virus, which normally does...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.21.9747

    authors: Han X,Kasahara N,Kan YW

    更新日期:1995-10-10 00:00:00

  • Characterization of a thyroid hormone receptor expressed in human kidney and other tissues.

    abstract::A cDNA encoding a specific form of thyroid hormone receptor expressed in human liver, kidney, placenta, and brain was isolated from a human kidney library. Identical clones were found in human placenta and HepG2 cDNA libraries. The cDNA encodes a 490-amino acid protein (Mr, 54,824). When expressed and translated in vi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.8.2781

    authors: Nakai A,Seino S,Sakurai A,Szilak I,Bell GI,DeGroot LJ

    更新日期:1988-04-01 00:00:00

  • Development of an in vitro mRNA decay system for Escherichia coli: poly(A) polymerase I is necessary to trigger degradation.

    abstract::Using a novel Escherichia coli in vitro decay system in which polysomes are the source of both enzymes and mRNA, we demonstrate a requirement for poly(A) polymerase I (PAP I) in mRNA turnover. The in vitro decay of two different mRNAs (trxA and lpp) is triggered by the addition of ATP only when polysomes are prepared ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.23.12926

    authors: Ingle CA,Kushner SR

    更新日期:1996-11-12 00:00:00

  • An example in surface area.

    abstract::For length and area, a central fact is that the value of the length of a curve or the area of a surface, as given by the Lebesgue theory, is at least as great as that given by the classical formula, whenever the latter has meaning. This is now found not to be valid in higher dimensions. We give an example of a continu...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.63.1.38

    authors: Goffman C

    更新日期:1969-05-01 00:00:00

  • Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis.

    abstract::Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to dete...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1408129111

    authors: Calligaris D,Caragacianu D,Liu X,Norton I,Thompson CJ,Richardson AL,Golshan M,Easterling ML,Santagata S,Dillon DA,Jolesz FA,Agar NY

    更新日期:2014-10-21 00:00:00

  • Apparent homology of expressed genes from wood-forming tissues of loblolly pine (Pinus taeda L.) with Arabidopsis thaliana.

    abstract::Pinus taeda L. (loblolly pine) and Arabidopsis thaliana differ greatly in form, ecological niche, evolutionary history, and genome size. Arabidopsis is a small, herbaceous, annual dicotyledon, whereas pines are large, long-lived, coniferous forest trees. Such diverse plants might be expected to differ in a large numbe...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1132171100

    authors: Kirst M,Johnson AF,Baucom C,Ulrich E,Hubbard K,Staggs R,Paule C,Retzel E,Whetten R,Sederoff R

    更新日期:2003-06-10 00:00:00

  • Transcription of a subset of human class II major histocompatibility complex genes is regulated by a nucleoprotein complex that contains c-fos or an antigenically related protein.

    abstract::Transcriptional regulation of the human major histocompatibility complex class II genes requires at least two upstream elements, the X and Y boxes, located in the -50- to -150-base-pair region of all class II promoters. The DRA and DPB promoters contain phorbol ester-responsive elements overlapping the 3' side of thei...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.10.4304

    authors: Ono SJ,Bazil V,Levi BZ,Ozato K,Strominger JL

    更新日期:1991-05-15 00:00:00

  • Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities.

    abstract::The activity of leukotriene A4 (LTA4) synthase in crude human leukocyte homogenates was found to have a similar requirement for Ca2+ and ATP as had been noted previously for 5-lipoxygenase activity. Purification of the 5-lipoxygenase using ammonium sulfate fractionation, AcA 44 gel-filtration chromatography, and HPLC ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.4.857

    authors: Rouzer CA,Matsumoto T,Samuelsson B

    更新日期:1986-02-01 00:00:00

  • Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.

    abstract::Signaling through beta-arrestins is a recently appreciated mechanism used by seven-transmembrane receptors. Because G protein-coupled receptor kinase (GRK) phosphorylation of such receptors is generally a prerequisite for beta-arrestin binding, we studied the roles of different GRKs in promoting beta-arrestin-mediated...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0409534102

    authors: Ren XR,Reiter E,Ahn S,Kim J,Chen W,Lefkowitz RJ

    更新日期:2005-02-01 00:00:00

  • Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy.

    abstract::Bone marrow mononuclear cells (BMC) from patients with ischemic cardiomyopathy (ICMP) show a reduced neovascularization capacity in vivo. NO plays an important role in neovascularization, and NO bioavailability is typically reduced in patients with ICMP. We investigated whether the impaired neovascularization capacity...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0604144103

    authors: Sasaki K,Heeschen C,Aicher A,Ziebart T,Honold J,Urbich C,Rossig L,Koehl U,Koyanagi M,Mohamed A,Brandes RP,Martin H,Zeiher AM,Dimmeler S

    更新日期:2006-09-26 00:00:00

  • Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening.

    abstract::A de novo mutation in the KCND2 gene, which encodes the Kv4.2 K+ channel, was identified in twin boys with intractable, infant-onset epilepsy and autism. Kv4.2 channels undergo closed-state inactivation (CSI), a mechanism by which channels inactivate without opening during subthreshold depolarizations. CSI dynamically...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1717082115

    authors: Lin MA,Cannon SC,Papazian DM

    更新日期:2018-04-10 00:00:00

  • Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells.

    abstract::The Abeta peptide of Alzheimer disease is derived from the proteolytic processing of the amyloid precursor proteins (APP), which are considered type I transmembrane glycoproteins. Recently, however, soluble forms of full-length APP were also detected in several systems including chromaffin granules. In this report we ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.15.8046

    authors: Efthimiopoulos S,Vassilacopoulou D,Ripellino JA,Tezapsidis N,Robakis NK

    更新日期:1996-07-23 00:00:00

  • Copy number alteration burden predicts prostate cancer relapse.

    abstract::Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discov...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 临床试验,杂志文章

    doi:10.1073/pnas.1411446111

    authors: Hieronymus H,Schultz N,Gopalan A,Carver BS,Chang MT,Xiao Y,Heguy A,Huberman K,Bernstein M,Assel M,Murali R,Vickers A,Scardino PT,Sander C,Reuter V,Taylor BS,Sawyers CL

    更新日期:2014-07-29 00:00:00

  • Entropy of dialogues creates coherent structures in e-mail traffic.

    abstract::We study the dynamic network of e-mail traffic and find that it develops self-organized coherent structures similar to those appearing in many nonlinear dynamic systems. Such structures are uncovered by a general information theoretic approach to dynamic networks based on the analysis of synchronization among trios of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0405728101

    authors: Eckmann JP,Moses E,Sergi D

    更新日期:2004-10-05 00:00:00

  • Designing amino acids to determine the local conformations of peptides.

    abstract::The local conformations of proteins and peptides are determined by the amino acid sequence. However, the 20 amino acids encoded by the genome allow the peptide backbone to fold into many conformations, so that even for a small peptide it becomes very difficult to predict the three-dimensional structure. By using empir...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.7.2649

    authors: Burgess AW

    更新日期:1994-03-29 00:00:00

  • Evolution of the immunoglobulin kappa light chain locus in the rabbit: evidence for differential gene conversion events.

    abstract::The rabbit kappa light chain gene family is characterized by the presence of two constant region (C kappa) genes; the C kappa 1 gene encodes the constant region of the principal rabbit immunoglobulin light chain, the C kappa 2 gene being not or very poorly expressed in domestic rabbits. There exist four major K1 allel...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.14.5180

    authors: Akimenko MA,Mariamé B,Rougeon F

    更新日期:1986-07-01 00:00:00

  • Autoregulation of the Raf-1 serine/threonine kinase.

    abstract::The Raf-1 serine/threonine kinase is a key protein involved in the transmission of many growth and developmental signals. In this report, we show that autoinhibition mediated by the noncatalytic, N-terminal regulatory region of Raf-1 is an important mechanism regulating Raf-1 function. The inhibition of the regulatory...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.16.9214

    authors: Cutler RE Jr,Stephens RM,Saracino MR,Morrison DK

    更新日期:1998-08-04 00:00:00

  • Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI.

    abstract::The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 (HP(129)Xe) make it attractive for a number of magnetic resonance applications; moreover, HP(129)Xe embodies an alternative to rare and nonrenewable (3)He. However, the ability to reliably and inexpensively produce large quant...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1306586110

    authors: Nikolaou P,Coffey AM,Walkup LL,Gust BM,Whiting N,Newton H,Barcus S,Muradyan I,Dabaghyan M,Moroz GD,Rosen MS,Patz S,Barlow MJ,Chekmenev EY,Goodson BM

    更新日期:2013-08-27 00:00:00

  • Mechanotransduction and strain amplification in osteocyte cell processes.

    abstract::A paradox in bone tissue is that tissue-level strains due to animal and human locomotion are too small to initiate intracellular chemical responses directly. A model recently was proposed to resolve this paradox, which predicts that the fluid flow through the pericellular matrix in the lacunar-canalicular porosity due...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0407429101

    authors: Han Y,Cowin SC,Schaffler MB,Weinbaum S

    更新日期:2004-11-23 00:00:00

  • The 3 × 120° rotary mechanism of Paracoccus denitrificans F1-ATPase is different from that of the bacterial and mitochondrial F1-ATPases.

    abstract::The rotation of Paracoccus denitrificans F1-ATPase (PdF1) was studied using single-molecule microscopy. At all concentrations of adenosine triphosphate (ATP) or a slowly hydrolyzable ATP analog (ATPγS), above or below Km, PdF1 showed three dwells per turn, each separated by 120°. Analysis of dwell time between steps s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2003163117

    authors: Zarco-Zavala M,Watanabe R,McMillan DGG,Suzuki T,Ueno H,Mendoza-Hoffmann F,García-Trejo JJ,Noji H

    更新日期:2020-11-24 00:00:00

  • Chromosomal organization of adrenergic receptor genes.

    abstract::The adrenergic receptors (ARs) (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. We have previously assigned the genes for ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.4.1516

    authors: Yang-Feng TL,Xue FY,Zhong WW,Cotecchia S,Frielle T,Caron MG,Lefkowitz RJ,Francke U

    更新日期:1990-02-01 00:00:00

  • Collagen biosynthesis in nonfibroblastic cell lines.

    abstract::Prolyl hydroxylase and other enzymes of collagen synthesis have been found in cloned cells, including epithelium, melanoma, liver, HeLa, pituitary, kidney, and neuroblastoma. The significance of collagen biosynthesis in nonfibroblastic cells lines is discussed. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.71.1.50

    authors: Langness U,Udenfriend S

    更新日期:1974-01-01 00:00:00

  • Multivalent weak interactions enhance selectivity of interparticle binding.

    abstract::Targeted drug delivery critically depends on the binding selectivity of cargo-transporting colloidal particles. Extensive theoretical work has shown that two factors are necessary to achieve high selectivity for a threshold receptor density: multivalency and weak interactions. Here, we study a model system of DNA-coat...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2003968117

    authors: Scheepers MRW,van IJzendoorn LJ,Prins MWJ

    更新日期:2020-09-15 00:00:00

  • In vitro reconstitution and steady-state analysis of the fatty acid synthase from Escherichia coli.

    abstract::Microbial fatty acid derivatives are emerging as promising alternatives to fossil fuel derived transportation fuels. Among bacterial fatty acid synthases (FAS), the Escherichia coli FAS is perhaps the most well studied, but little is known about its steady-state kinetic behavior. Here we describe the reconstitution of...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1110852108

    authors: Yu X,Liu T,Zhu F,Khosla C

    更新日期:2011-11-15 00:00:00

  • Spontaneous wettability patterning via creasing instability.

    abstract::Surfaces with patterned wettability contrast are important in industrial applications such as heat transfer, water collection, and particle separation. Traditional methods of fabricating such surfaces rely on microfabrication technologies, which are only applicable to certain substrates and are difficult to scale up a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1522700113

    authors: Chen D,McKinley GH,Cohen RE

    更新日期:2016-07-19 00:00:00

  • Water does not flow across the tight junctions of MDCK cell epithelium.

    abstract::Although it has been known for decades that the tight junctions of fluid-transporting epithelia are leaky to ions, it has not been possible to determine directly whether significant transjunctional water movement also occurs. An optical microscopic technique was developed for the direct visualization of the flow veloc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.11.6526

    authors: Kovbasnjuk O,Leader JP,Weinstein AM,Spring KR

    更新日期:1998-05-26 00:00:00

  • Platelet and osteoclast beta3 integrins are critical for bone metastasis.

    abstract::Mice with a targeted deletion of beta3 integrin were used to examine the process by which tumor cells metastasize and destroy bone. Injection of B16 melanoma cells into the left cardiac ventricle resulted in osteolytic bone metastasis in 74% of beta3+/+ mice by 14 days. In contrast, only 4% of beta3-/- mice developed ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2234372100

    authors: Bakewell SJ,Nestor P,Prasad S,Tomasson MH,Dowland N,Mehrotra M,Scarborough R,Kanter J,Abe K,Phillips D,Weilbaecher KN

    更新日期:2003-11-25 00:00:00