320 research outputs found
Phagocytic plasma cells in a patient with multiple myeloma
Phagocytosis of blood cells by malignant plasma cells in multiple myeloma is an extremely rare condition. Here we present a 39-year-old woman with multiple myeloma. Bone marrow smear showed an extensive phagocytosis of erythrocytes and platelets by myeloma cells
Facilitated engraftment of human hematopoietic cells in severe combined immunodeficient mice following a single injection of Cl²MDP liposomes
Transplantation of normal and malignant human hematopoietic cells into severe combined immunodeficient (SCID) mice allows for evaluation of long-term growth abilities of these cells and provides a preclinical model for therapeutic interventions. However, large numbers of cells are required for successful engraftment in preirradiated mice due to residual graft resistance, that may be mediated by cells from the mononuclear phagocytic system. Intravenous (i.v.) injection of liposomes containing dichloromethylene diphosphonate (Cl2MDP) may eliminate mouse macrophages in spleen and liver. In this study outgrowth of acute myeloid leukemia (AML) cells and umbilical cord blood (UCB) cells in SCID mice conditioned with a single i.v. injection of Cl2MDP liposomes in addition to sublethal total body irradiation (TBI) was compared to outgrowth of these cells in SCID mice that had received TBI alone. A two- to 10-fold increase in outgrowth of AML cells was observed in four cases of AML. Administration of 107 UCB cells reproducibly engrafted SCID mice that had been conditioned with Cl2MDP liposomes and TBI, whereas human cells were not detected in mice conditioned with TBI alone. As few as 2 x 104 purified CD34+ UCB cells engrafted in all mice treated with Cl2MDP liposomes. In SCID mice treated with macrophage depletion unexpected graft failures were not observed. Histological examination of the spleen showed that TBI and Cl2MDP liposomes i.v. resulted in a transient elimination of all macrophage subsets in the spleen, whereas TBI had a minor effect. Cl2MDP liposomes were easy to use and their application was not associated with appreciable side-effects. Cl2MDP liposome pretreatment in combination with TBI allows for reproducible outgrowth of high numbers of human hematopoietic cells in SCID mice
CD20 and CD40 mediated mitogenic responses in B-lineage acute lymphoblastic leukaemia
Activation of CD20, a cross-membrane ion channel, induces cell cycle progression from G0 to G1 in B lymphocytes. Subsequent activation of CD40, a membrane receptor of the nerve growth factor receptor superfamily, transits the B cells to the S phase. CD40 may also act synergistically in combination with IL-4 (B lymphocytes) or IL-3/IL-7 (B-cell precursors). We investigated the proliferative responses of B-lineage acute lymphoblastic leukaemia (ALL) cells to CD20/CD40 activation. In 18/56 ALL cases, CD20 activation resulted in significant increases in DNA synthesis. Similar, although more moderate, effects were seen of activation of CD40 in 10/44 cases. Responses to CD20 or CD40 activation were independent of co-stimulation with IL-3, IL-4 or IL-7, and various cocktails of the different growth stimuli did not act synergistically
Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia
BACKGROUND. In severe congenital neutropenia the maturation of myeloid
progenitor cells is arrested. The myelodysplastic syndrome and acute
myeloid leukemia develop in some patients with severe congenital
neutropenia. Abnormalities in the signal-transduction pathways for
granulocyte colony-stimulating factor (G-CSF) may play a part in the
progression to acute myeloid leukemia. METHODS. We isolated genomic DNA
and RNA from hematopoietic cells obtained from two patients with acute
myeloid leukemia and histories of severe congenital neutropenia. The
nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor
were amplified by means of the polymerase chain reaction and sequenced.
Murine myeloid 32D.C10 cells were transfected with complementary DNA
encoding the wild-type or mutant G-CSF receptors and tested for their
responses to G-CSF. RESULTS. Point mutations in the gene for the G-CSF
receptor were identified in both patients. The mutations, a substitution
of thymine for cytosine at the codon for glutamine at position 718
(Gln718) in one patient and at the codon for glutamine at position
731(Gln731) in the other, caused a truncation of the C-terminal
cytoplasmic region of the receptor. Both mutant and wild-type genes for
the G-CSF receptor were present in leukemic cells from the two patients.
In one patient, the mutation was also found in the neutropenic stage,
before the progression to acute myeloid leukemia. The 32D.C10 cells
expressing mutant receptors had abnormally high proliferative responses
but failed to mature when cultured in G-CSF. The mutant G-CSF receptors
also interfered with terminal maturation mediated by the wild-type G-CSF
receptor in the 32D.C10 cells that coexpressed the wild-type and mutant
receptors. CONCLUSIONS. Mutations in the gene for the G-CSF receptor that
interrupt signals required for the maturation of myeloid cells are
involved in the pathogenesis of severe congenital neutropenia and
associated with the progression to acute myeloid leukemia
Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation
The granulocyte colony-stimulating factor receptor (G-CSF-R) transduces
signals important for the proliferation and maturation of myeloid
progenitor cells. To identify functionally important regions in the
cytoplasmic domain of the G-CSF-R, we compared the actions of the
wild-type receptor, two mutants, and a natural splice variant in
transfectants of the mouse pro-B cell line BAF3 and two myeloid cell
lines, 32D and L-GM. A region of 55 amino acids adjacent to the
transmembrane domain was found to be sufficient for generating a growth
signal. The immediate downstream sequence of 30 amino acids substantially
enhanced the growth signaling in the three cell lines. In contrast, the
carboxy-terminal part of 98 amino acids strongly inhibited growth
signaling in the two myeloid cell lines but not in BAF3 cells. Truncation
of this region lead to an inability of the G-CSF-R to transduce maturation
signals in L-GM cells. An alternative carboxy tail present in a splice
variant of the G-CSF-R also inhibited growth signaling, notably in both
the myeloid cells and BAF3 cells, but appeared not to be involved in
maturation
Retroviral Integration Mutagenesis in Mice and Comparative Analysis in Human AML Identify Reduced PTP4A3 Expression as a Prognostic Indicator
Acute myeloid leukemia (AML) results from multiple genetic and epigenetic aberrations, many of which remain unidentified. Frequent loss of large chromosomal regions marks haplo-insufficiency as one of the major mechanisms contributing to leukemogenesis. However, which haplo-insufficient genes (HIGs) are involved in leukemogenesis is largely unknown and powerful experimental strategies aimed at their identification are currently lacking. Here, we present a new approach to discover HIGs, using retroviral integration mutagenesis in mice in which methylated viral integration sites and neighbouring genes were identified. In total we mapped 6 genes which are flanked by methylated viral integration sites (mVIS). Three of these, i.e., Lrmp, Hcls1 and Prkrir, were up regulated and one, i.e., Ptp4a3, was down regulated in the affected tumor. Next, we investigated the role of PTP4A3 in human AML and we show that PTP4A3 expression is a negative prognostic indicator, independent of other prognostic parameters. In conclusion, our novel strategy has identified PTP4A3 to potentially have a role in AML, on one hand as a candidate HIG contributing to leukemogenesis in mice and on the other hand as a prognostic indicator in human AML
Tyrosine kinase receptor RON functions downstream of the erythropoietin
Erythropoietin (EPO) is required for cell survival during differentiation
and for progenitor expansion during stress erythropoiesis. Although
signaling pathways may couple directly to docking sites on the EPO
receptor (EpoR), additional docking molecules expand the signaling
platform of the receptor. We studied the roles of the docking molecules
Grb2-associated binder-1 (Gab1) and Gab2 in EPO-induced signal
transduction and erythropoiesis. Inhibitors of phosphatidylinositide
3-kinase and Src kinases suppressed EPO-dependent phosphorylation of Gab2.
In contrast, Gab1 activation depends on recruitment and phosphorylation by
the tyrosine kinase receptor RON, with which it is constitutively
associated. RON activation induces the phosphorylation of Gab1,
mitogen-activated protein kinase (MAPK), and protein kinase B (PKB) but
not of signal transducer and activator of transcription 5 (Stat5). RON
activation was sufficient to replace EPO in progenitor expansion but not
in differentiation. In conclusion, we elucidated a novel mechanism
specifically involved in the expansion of erythroblasts involving RON as a
downstream target of the Epo
Commentaire
Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch–Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death (‘primary refractoriness’). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML
Density fluctuations and single-particle dynamics in liquid lithium
The single-particle and collective dynamical properties of liquid lithium
have been evaluated at several thermodynamic states near the triple point. This
is performed within the framework of mode-coupling theory, using a
self-consistent scheme which, starting from the known static structure of the
liquid, allows the theoretical calculation of several dynamical properties.
Special attention is devoted to several aspects of the single-particle
dynamics, which are discussed as a function of the thermodynamic state. The
results are compared with those of Molecular Dynamics simulations and other
theoretical approaches.Comment: 31 pages (in preprint format), 14 figures. Submitted to Phys. Rev.
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