18 research outputs found
Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target
Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malig- nancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epi- genetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.Aggressiivinen NK-soluleukemia (ANKL) on elimistön luonnolliseen puolustusjĂ€rjestelmÀÀn kuuluvien luonnollisten tappajasolujen eli natural killer (NK) âsolujen verisyöpĂ€ eli leukemia. ANKL:aan sairastuneet potilaat sĂ€ilyvĂ€t kĂ€ytössĂ€ olevilla solunsalpaaja- ja kantasolusiirtohoidoilla elossa keskimÀÀrin vain joitakin kuukausia. Erityisesti aasialaisvĂ€estössĂ€ esiintyvĂ€n ANKL:n lisĂ€ksi NK-soluisiin syöpiin kuuluu Suomessakin harvinaisina tavattavia NK/T-soluisia lymfoomia. ANKL:n taustalla olevia hankittuja geenimuutoksia eli mutaatioita ei ole aiemmin selvitetty laajamittaisesti.
Tutkimuksessa selvitimme ANKL:n tautimekanismeja kartoittamalla 14 potilaan syöpÀsolujen geenimuutokset perimÀn proteiineja koodaavien geenien osalta ja tutkimalla pahanlaatuisten NK-solujen herkkyyttÀ yli 400 lÀÀkeaineelle.
Löysimme ANKL-potilaiden soluista geenimuutoksia etenkin STAT3- ja DDX3X-geeneissÀ, joita kumpiakin oli yli viidenneksellÀ potilaista. STAT3-mutaatioita on aiemmin todettu suurten granulaaristen lymfosyyttien (LGL) leukemiassa, sekÀ useissa muissakin T- ja NK-soluista lÀhtöisin olevissa syövissÀ. STAT3-mutaatiot ANKL:ssa viittaavat osin yhteisiin tautimekanismeihin nÀiden sukulaistautien kanssa. Kun yhdistimme ANKL-potilaiden geenitietoa aiemmin julkaistujen NK//T-solulymfoomapotilaista tuotettujen aineistojen kanssa, havaitsimme NK-soluisille syöville yhteisiÀ JAK-STAT-signalointigeenien monistumia.
Etsimme myös potentiaalisia lÀÀkeaineita NK-soluisten syöpien hoitoon testaamalla pahanlaatuisten NK-solujen herkkyyttÀ yli 400 lÀÀkeaineelle. Havaitsimme NK-solujen olevan poikkeuksellisen herkkiÀ JAK-tyrosiinikinaasin ja BCL-perheen solukuolemaa sÀÀtelevien proteiinien estÀjille. JAK-estÀjillÀ pyritÀÀn hiljentÀmÀÀn samaa JAK-STAT-signalointireittiÀ, josta löysimme geneettisiÀ muutoksia ANKL-potilailla. Myeloproliferatiivisten sairauksien ja nivelreuman hoidossa kÀytettÀvillÀ JAK-estÀjillÀ voitaisiin mahdollisesti tehostaa NK-soluisten syöpien hoitoa hyödyntÀmÀllÀ kyseisen solutyypin voimakasta riippuvuutta JAK-STAT-signaloinnin aktiivisuudesta.
Tutkimuksemme valottaa geenitason muutoksia aiemmin tautimekanismeiltaan tuntemattomassa ANKL:ssa. LÀÀkeherkkyysseulonnan avulla pystyimme tunnistamaan potentiaalisia lÀÀkeaineita ajatellen hoitokokeiluja harvinaisessa ANKL:ssa, jossa kliinisiÀ lÀÀketutkimuksia pystytÀÀn harvoin toteuttamaan
Observation of Large CP Violation in the Neutral B Meson System
We present a measurement of the Standard Model CP violation parameter sin
2phi_1 based on a 29.1 fb^{-1} data sample collected at the Upsilon(4S)
resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider.
One neutral B meson is fully reconstructed as a J/psi Ks, psi(2S) Ks, chi_c1
Ks, eta_c Ks, J/psi K_L or J/psi K^{*0} decay and the flavor of the
accompanying B meson is identified from its decay products. From the asymmetry
in the distribution of the time intervals between the two B meson decay points,
we determine sin 2phi_1 = 0.99 +- 0.14(stat) +- 0.06(syst). We conclude that we
have observed CP violation in the neutral B meson system.Comment: 4 figures, to appear in Phys. Rev. Letter
Measurement of B0d - B0d-bar mixing rate from the time evolution of dilepton events at the Upsilon(4S)
We report a determination of the B0d - B0d-bar mixing parameter Delta-m_d
based on the time evolution of dilepton yields in Upsilon(4S) decays. The
measurement is based on a 5.9 /fb data sample collected by the Belle detector
at KEKB. The proper-time difference distributions for same-sign and
opposite-sign dilepton events are simultaneously fitted to an expression
containing Delta-m_d as a free parameter. Using both muons and electrons, we
obtain Delta-m_d = 0.463 +- 0.008(stat.) +- 0.016(sys.) ps^{-1} This is the
first determination of Delta-m_d from time evolution measurements at the
Upsilon(4S). We also place limits on possible CPT violations.Comment: 12 pages, 2 figure
Measurement of the CP Violation Parameter sin(2phi_1) in B^0_d Meson Decays
We present a measurement of the Standard Model CP violation parameter
sin(2phi_1) based on a 10.5 fb^{-1} data sample collected at the Upsilon(4S)
resonance with the Belle detector at the KEKB asymmetric e+e- collider. One
neutral B meson is reconstructed in the J/psi K_S, psi(2S) K_S, chi_{c1} K_S,
eta_c K_S, J/psi K_L or J/psi pi^0 CP-eigenstate decay channel and the flavor
of the accompanying B meson is identified from its charged particle decay
products. From the asymmetry in the distribution of the time interval between
the two B-meson decay points, we determine sin(2phi_1) = 0.58 +0.32-0.34 (stat)
+0.09-0.10 (syst).Comment: LaTex, 13 pages, 3 figures, submitted to P.R.
An Improved Measurement of Mixing-induced CP Violation in the Neutral B Meson System
We present an improved measurement of the standard model CP violation
parameter sin2phi_1 (also known as sin2beta) based on a sample of 85 times 10^6
B Bbar pairs collected at the Upsilon(4S) resonance with the Belle detector at
the KEKB asymmetric-energy e+e- collider. One neutral B meson is reconstructed
in a J/psi K_S, psi(2S) K_S, chi_{c1} K_S, eta_c K_S, J/psi K^{*0}, or J/psi
K_L CP-eigenstate decay channel and the flavor of accompanying B meson is
identified from itsdecay products. From the asymmetry in the distribution of
the time intervals between the two B meson decay points, we obtain sin2phi_1 =
0.719 +/- 0.074(stat) +/- 0.035(syst). We also report measurements of CP
violation parameters for the related B^0 -> J/psi pi^0 decay mode and the
penguin-dominated processes B^0 -> eta' K_S, phi K_S and K^+K^- K_S.Comment: 11 pages, 4 figures, 4 tables, contributed to ICHEP200
Study of CP-Violating Asymmetries in B0 -> pi+pi- Decays
We present a measurement of CP-violating asymmetries in B0 -> pi+pi- decays
based on a 41.8 fb-1 data sample collected at the Upsilon(4S) resonance with
the Belle detector at the KEKB asymmetric-energy e+e- collider. We fully
reconstruct one neutral B meson as a B0 -> pi+pi- CP eigenstate and identify
the flavor of the accompanying B meson from its decay products. From the
asymmetry in the distribution of the time intervals between the two B meson
decay points, we obtain the CP-violating asymmetry parameters Spipi = -1.21
+0.38/-0.27(stat) +0.16/-0.13(syst) and Apipi = +0.94 +0.25/-0.31(stat) +/-
0.09(syst).Comment: 9 pages, 2 figures, accepted for publication in Physical Review
Letter
Observation of B->J/psi K1(1270)
We report the first observation of the exclusive decay process B->J/psi
K1(1270) using a sample of 11.2M BBbar meson pairs collected in the Belle
detector at the KEKB asymmetric e+e- collider. We measure branching fractions
of Bf(B0 -> J/psi K10(1270) = (1.30 +-0.34 +-0.31)x10^-3 and Bf(B+ -> J/psi
K1+(1270) = (1.80 +-0.34 +-0.39)x10-3, where the first error is statistical and
the second systematic. These modes constitute approximately 15% of the total
number of B -> J/psiX decays. No evidence is seen for B -> J/psi K1(1400) and
we set an upper limit on this branching fraction. The K1(1270) -> K0pi+pi-
decays have a substantial K0rho0 intermediate state component that may be
useful for CP violation studies.Comment: Submitted to Physical Review Letter
The Physics of the B Factories
This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C