Targeting self-renewal pathways in myeloid malignancies

A fundamental property of hematopoietic stem cells (HSCs) is the ability to self-renew. This is a complex process involving multiple signal transduction cascades which control the fine balance between self-renewal and differentiation through transcriptional networks. Key activators/regulators of self-renewal include chemokines, cytokines and morphogens which are expressed in the bone marrow niche, either in a paracrine or autocrine fashion, and modulate stem cell behaviour. Increasing evidence suggests that the downstream signaling pathways induced by these ligands converge at multiple levels providing a degree of redundancy in steady state hematopoiesis. Here we will focus on how these pathways cross-talk to regulate HSC self-renewal highlighting potential therapeutic windows which could be targeted to prevent leukemic stem cell self-renewal in myeloid malignancies

Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy

Correction: CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

Correction to: Leukemia https://doi.org/10.1038/s41375-019-0684-

Σ−p\Sigma^- p emission rates in K−K^- absorptions at rest on 6^6Li, 7^7Li, 9^{9}Be, 13^{13}C and 16^{16}O

An experimental study of the $K^-_{stop}A\rightarrow \Sigma^- p A'$ reaction on $A=^6$Li, $^7$Li, $^9$Be, $^{13}$C and $^{16}$O $p$-shell nuclei is presented. The data were collected by the FINUDA spectrometer operating at the DA$\Phi$NE $\phi$-factory (LNF-INFN, Italy). Emission rates for the reaction in the mentioned nuclei are measured and compared with the few existing data. The spectra of several observables are discussed; indications of Quasi-Free absorptions by a $(np)$ pair embedded in the $A$ nucleus can be obtained from the study of the missing mass distributions.Comment: Version accepted by PR

A study of the proton spectra following the capture of K−K^- in 6^6Li and 12^{12}C with FINUDA

Momenta spectra of protons emitted following the capture of $K^-$ in $^6$Li and $^{12}$C have been measured with 1% resolution. The $^{12}$C spectrum is smooth whereas for $^6$Li a well defined peak appears at about 500 MeV/$c$. The first observation of a structure in this region was identified as a strange tribaryon or, possibly, a $\bar K$-nuclear state. The peak is correlated with a $\pi^-$ coming from $\Sigma^-$ decay in flight, selected by setting momenta larger than 275 MeV/$c$. The $\Sigma^-$ could be produced, together with a 500 MeV/$c$ proton, by the capture of a $K^-$ in a deuteron-cluster substructure of the $^6$Li nucleus. The capture rate for such a reaction is (1.62\pm 0.23_{stat} ^{+0.71}_{-0.44}(sys))%/K^-_{stop}, in agreement with the existing observations on $^4$He targets and with the hypothesis that the $^6$Li nucleus can be interpreted as a $(d+\alpha)$ cluster.Comment: 21 pages, 10 figures. Accepted for publication in NP

Proton spectra from Non-Mesonic Weak Decay of p-shell Lambda-Hypernuclei and evidence for the two-nucleon induced process

New spectra from the FINUDA experiment of the Non Mesonic Weak Decay (NMWD) proton kinetic energy for 9(Lambda)Be, 11(Lambda)B, 12(Lambda)C, 13(Lambda)C, 15 (Lambda)N and 16(Lambda)O are presented and discussed along with the published data on 5(Lambda)He and 7(Lambda)Li. Exploiting the large mass number range and the low energy threshold (15 MeV) for the proton detection of FINUDA, an evaluation of both Final State Interactions (FSI) and the two nucleon induced NMWD contributions to the decay process has been done. Based on this evaluation, a linear dependence of FSI on the hypernuclear mass number A is found and for the two nucleon stimulated decay rate the experimental value of Gamma2/Gammap=0.43+-0.25 is determined for the first time. A value for the two nucleon stimulated decay rate to the total decay rate Gamma2/GammaNMWD=0.24+-0.10 is also extracted.Comment: 11 pages and 2 figure

Production of Λ6^{6}_{\Lambda}H and Λ7^{7}_{\Lambda}H with the (Kstop−^{-}_{stop},π+\pi^+) reaction

The production of neutron rich $\Lambda$-hypernuclei via the ($K^-_stop$,$\pi^+$) reaction has been studied using data collected with the FINUDA spectrometer at the DA$\Phi$NE $\phi$-factory (LNF). The analysis of the inclusive $\pi^+$ momentum spectra is presented and an upper limit for the production of $^6_\Lambda$H and $^7_\Lambda$H from $^6$Li and $^7$Li, is assessed for the first time.Comment: 11 pages, 3 figures. Accepted for publication in PL

Hypernuclear spectroscopy with K−^- at rest on 7^7Li, 9^9Be, 13^{13}C and 16^{16}O

The FINUDA experiment collected data to study the production of hypernuclei on different nuclear targets. The hypernucleus formation occurred through the strangeness-exchange reaction K^-_{stop} + \; ^AZ \rightarrow \; ^A_{\Lambda}Z + \pi^-. From the analysis of the momentum of the emerging $\pi^-$, binding energies and formation probabilities of $^7_{\Lambda}$Li, $^9_{\Lambda}$Be, $^{13}_{\Lambda}$C and $^{16}_{\Lambda}$O have been measured and are here presented. The behavior of the formation probability as a function of the atomic mass number A is also discussed.Comment: Accepted for publication in PL