High immunoproteasome activity and sXBP1 in pediatric precursor B-ALL predicts sensitivity towards proteasome inhibitors

Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome beta 5i induces cytotoxicity in BCP-ALL containing high beta 5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with beta 2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to beta 5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses.Bio-organic Synthesi

CXCR4 mediates leukemic cell migration and survival in the testicular microenvironment

The testis is the second most frequent extramedullary site of relapse in pediatric acute lymphoblastic leukemia (ALL). The mechanism for B-cell (B) ALL cell migration towards and survival within the testis remains elusive. Here, we identified CXCL12-CXCR4 as the leading signaling axis for B-ALL cell migration and survival in the testicular leukemic niche. We combined analysis of primary human ALL with a novel patient-derived xenograft (PDX)-ALL mouse model with testicular involvement. Prerequisites for leukemic cell infiltration in the testis were pre-pubertal age of the recipient mice, high surface expression of CXCR4 on PDX-ALL cells, and CXCL12 secretion from the testicular stroma. Analysis of primary pediatric patient samples revealed that CXCR4 was the only chemokine receptor being robustly expressed on B-ALL cells both at the time of diagnosis and relapse. In affected patient testes, leukemic cells localized within the interstitial space in close proximity to testicular macrophages. Mouse macrophages isolated from affected testes, in the PDX model, revealed a macrophage polarization towards a M2-like phenotype in the presence of ALL cells. Therapeutically, blockade of CXCR4-mediated functions using an anti-CXCR4 antibody treatment completely abolished testicular infiltration of PDX-ALL cells and strongly impaired the overall development of leukemia. Collectively, we identified a pre-pubertal condition together with high CXCR4 expression as factors affecting the leukemia permissive testicular microenvironment. We propose CXCR4 as a promising target for therapeutic prevention of testicular relapses in childhood B-ALL

γ-Catenin-Dependent Signals Maintain BCR-ABL1⁺ B Cell Acute Lymphoblastic Leukemia.

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1 <sup>+</sup> B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1 <sup>+</sup> B-ALL

Search for antihelium in cosmic rays

The Alpha Magnetic Spectrometer (AMS) was flown on the space shuttle Discovery during flight STS-91 in a 51.7 degree orbit at altitudes between 320 and 390 km. A total of 2.86 * 10^6 helium nuclei were observed in the rigidity range 1 to 140 GV. No antihelium nuclei were detected at any rigidity. An upper limit on the flux ratio of antihelium to helium of < 1.1 * 10^-6 is obtained.Comment: 18 pages, Latex, 9 .eps figure

Protons in near earth orbit

The proton spectrum in the kinetic energy range 0.1 to 200 GeV was measured by the Alpha Magnetic Spectrometer (AMS) during space shuttle flight STS-91 at an altitude of 380 km. Above the geomagnetic cutoff the observed spectrum is parameterized by a power law. Below the geomagnetic cutoff a substantial second spectrum was observed concentrated at equatorial latitudes with a flux ~ 70 m^-2 sec^-1 sr^-1. Most of these second spectrum protons follow a complicated trajectory and originate from a restricted geographic region.Comment: 19 pages, Latex, 7 .eps figure

A Study of Cosmic Ray Secondaries Induced by the Mir Space Station Using AMS-01

The Alpha Magnetic Spectrometer (AMS-02) is a high energy particle physics experiment that will study cosmic rays in the $\sim 100 \mathrm{MeV}$ to $1 \mathrm{TeV}$ range and will be installed on the International Space Station (ISS) for at least 3 years. A first version of AMS-02, AMS-01, flew aboard the space shuttle \emph{Discovery} from June 2 to June 12, 1998, and collected $10^8$ cosmic ray triggers. Part of the \emph{Mir} space station was within the AMS-01 field of view during the four day \emph{Mir} docking phase of this flight. We have reconstructed an image of this part of the \emph{Mir} space station using secondary $\pi^-$ and $\mu^-$ emissions from primary cosmic rays interacting with \emph{Mir}. This is the first time this reconstruction was performed in AMS-01, and it is important for understanding potential backgrounds during the 3 year AMS-02 mission.Comment: To be submitted to NIM B Added material requested by referee. Minor stylistic and grammer change

Measurement of W Polarisation at LEP

The three different helicity states of W bosons produced in the reaction e+ e- -> W+ W- -> l nu q q~ at LEP are studied using leptonic and hadronic W decays. Data at centre-of-mass energies \sqrt s = 183-209 GeV are used to measure the polarisation of W bosons, and its dependence on the W boson production angle. The fraction of longitudinally polarised W bosons is measured to be 0.218 \pm 0.027 \pm 0.016 where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model expectation

Search for Anomalous Couplings in the Higgs Sector at LEP

Anomalous couplings of the Higgs boson are searched for through the processes e^+ e^- -> H gamma, e^+ e^- -> e^+ e^- H and e^+ e^- -> HZ. The mass range 70 GeV < m_H < 190 GeV is explored using 602 pb^-1 of integrated luminosity collected with the L3 detector at LEP at centre-of-mass energies sqrt(s)=189-209 GeV. The Higgs decay channels H -> ffbar, H -> gamma gamma, H -> Z\gamma and H -> WW^(*) are considered and no evidence is found for anomalous Higgs production or decay. Limits on the anomalous couplings d, db, Delta(g1z), Delta(kappa_gamma) and xi^2 are derived as well as limits on the H -> gamma gamma and H -> Z gamma decay rates

Measurement of W Polarisation at LEP

The three different helicity states of W bosons produced in the reaction e+ e- -> W+ W- -> l nu q q~ at LEP are studied using leptonic and hadronic W decays. Data at centre-of-mass energies \sqrt s = 183-209 GeV are used to measure the polarisation of W bosons, and its dependence on the W boson production angle. The fraction of longitudinally polarised W bosons is measured to be 0.218 \pm 0.027 \pm 0.016 where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model expectation

Neutral-Current Four-Fermion Production in e+e- Interactions at LEP

Neutral-current four-fermion production, e+e- -> ffff is studied in 0.7/fb of data collected with the L3 detector at LEP at centre-of-mass energies root(s)=183-209GeV. Four final states are considered: qqvv, qqll, llll and llvv, where l denotes either an electron or a muon. Their cross sections are measured and found to agree with the Standard Model predictions. In addition, the e+e- -> Zgamma* -> ffff process is studied and its total cross section at the average centre-of-mass energy 196.6GeV is found to be 0.29 +/- 0.05 +/- 0.03 pb, where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model prediction of 0.22 pb. Finally, the mass spectra of the qqll final states are analysed to search for the possible production of a new neutral heavy particle, for which no evidence is found