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F Smadja-Joffe

Publications and source records attributed to F Smadja-Joffe.

At least 37 records · Page 2Linked to original sources
PubMed1988

Histopathologic studies on myeloproliferative sarcoma virus (MPSV) induced leukemias and hemangiosarcoma in Jar-2 rats.

It is well known that MPSV induces myeloproliferative syndrome (MPS) in mice. Intravenous one shot inoculation of myeloproliferative sarcoma virus (MPSV) with Friend murine leukemia virus (F-MuLV) as a helper in newborn Jar-2 rats (on the second neonatal day) yielded hematopoietic malignancies in all the treated rats (25/25 rats) after 2 weeks' latency. MPS appeared from the 14th day in 14 rats. In the midst of the myeloproliferative field of the spleen and bone marrow, myeloblastic or myeloblastic-erythroblastic foci were observed. From 19th day, acute myeloblastic leukemia occurred in 3 rats and erythroleukemia in 8 rats. MPSV induced first MPS which remained as such or later developed into acute leukemia. Myelofibrosis as seen in mice was not observed. In addition, hemangiosarcoma of the brain, spinal cord and spleen appeared in 15 rats from the 24th day, and were often multiple. MPSV can yield the tumor only in newborn rats, and target cells of MPSV are not only hematopoietic cells but also endothelial cells of the brain, spinal cord and occasionally spleen.

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PubMed1987

Abnormal splenic megakaryopoiesis in MPSV-induced myeloproliferative disease.

The myeloproliferative sarcoma virus (MPSV) induces a murine myeloproliferative syndrome characterized by an erythromyelemia, an anemia, a thrombocytopenia associated with a myeloproliferation in the spleen and a splenic and medullar fibrosis. We have used the in-vitro plasma clot technique to measure megakaryocytic precursors in the spleen and bone-marrow of MPSV-infected mice. We report that megakaryocytic colonies are increased, in number (X75), in concentration (X9) and in size, in the spleen but not in the bone-marrow of neoplastic mice. Furthermore, these splenic precursors are hypersensitive to growth factors present in the anemic mouse serum used in the culture system. These data show that the thrombocytopenia observed in the MPSV-induced neoplasia does not result from a lack of megakaryocyte precursors, but rather from an excess of megakaryocyte destruction. This ineffective splenic megakaryopoiesis associated with the presence of a massive splenic fibrosis make the MPS-induced neoplasia a suitable model for studying the perturbation of megakaryopoiesis in myeloproliferative syndrome associated with fibrosis.

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PubMed1986

Isolation from the spleen of myeloproliferative sarcoma virus-infected mice of a myelomonocytic tumor cell line secreting hematopoietic colony stimulating factors.

Clonogenic tumor cells were detected in the spleen of DBA/2 mice infected with the myeloproliferative sarcoma virus (MPSV). These cells could be isolated because of their ability to proliferate on the greater omentum of sublethally irradiated isogenic recipient mice. We have established a permanent suspension myelomonocytic cell line in vitro (TE8), from a tumor obtained after subcutaneous transplantation of the omental tumor masses. The TE8 cells are clonogenic in semi-solid medium containing agarose. The colonies thus obtained gave rise to myelomonocytic cell lines growing in suspension in liquid medium. One of those cloned cell lines, C1(1011) was studied in details. It is exclusively composed of initial donor cells, it is tumorigenic in vivo, clonogenic in vitro and produces MPSV. It also secretes a colony stimulating activity (CSA), and an activity termed mixed colony promoting activity (MPA), which enables pluripotent hematopoietic stem cells to proliferate and differentiate. It differentiates through the granulomacrophage cell line independently of exogenous factors other than those which may be present in the serum.

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PubMed1986

The myeloproliferative sarcoma virus retains transforming functions after introduction of a dominant selectable marker gene.

The dominant neomycin resistance gene (neoR) was introduced into the genome of the myeloproliferative sarcoma virus (MPSV), a replication-defective retrovirus carrying the mos oncogene. The resulting selectable neoR-MPSV virus did not lose its acute transforming property, unlike the results of attempts by other groups to insert marker genes into oncogenic viruses. NeoR-MPSV DNA was used to generate infectious virus by transfection followed by rescue with Friend or Moloney murine leukaemia virus. Infection of fibroblasts with this virus resulted in morphologically transformed cells which were resistant to the neomycin analogue G418. Segregation of the two functions (transformation and G418 resistance) was not observed in more than 500 independent viral transfers to fibroblasts. Furthermore, neoR-MPSV retained the leukaemogenesis-inducing properties of the wild-type virus. Myeloproliferation and G418-resistance transfer did not segregate after passage in mice.

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PubMed1986

Ectopic hematopoiesis in peritoneal tumor nodules induced by the myeloproliferative sarcoma virus in DBA/2 mice.

Tumor nodules composed of fibroblasts, large undifferentiated cells, granulocytes, and small lymphocytes develop in the spleens of adult DBA/2 mice infected with the myeloproliferative sarcoma virus (MPSV). They spread thereafter in the organism, and at the terminal stage of the disease they are especially numerous on the peritoneal membrane. The present study, performed on those tumor nodules to avoid contamination by exogenous hematopoietic cells, demonstrated that they were sites of granulopoiesis, which may have occurred via the local differentiation of granulomacrophage precursor cells (GM-CFC) and perhaps also from pluripotent hematopoietic stem cells, since these two populations were present in the tumor nodules (25 +/- 11 and 13 +/- 10, respectively, per 5-10(5) cells). Almost all (88%) those GM-CFC were able to clone in vitro without added colony-stimulating factor. A comparative study with the Moloney murine sarcoma virus-induced tumor indicated that the local production of hematopoiesis-stimulating factors was not sufficient to allow such ectopic granulopoiesis. These results imply the presence of a specific hematopoietic microenvironment in the MPSV-induced tumor nodules.

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PubMed1985

In vitro induction of CFU-S proliferation by a non viral splenic activity from myeloproliferative sarcoma virus infected mice.

The myeloproliferative sarcoma virus (MPSV) induces a myeloproliferative syndrome in DBA/2 mice. It is characterized by a considerable increase in the number (100-fold) and in the concentration (10-fold) of pluripotent hematopoietic stem cells detected in vivo (CFU-S) in the spleens of infected animals. Prior studies have shown the presence of a mixed-colony promoting activity (MPA) in neoplastic spleens. In the presence of a small quantity of erythropoietin, MPA induces the proliferation and differentiation of pluripotent hematopoietic stem cells, detected in vitro (Mix-CFU). We tested the effect of factors produced by neoplastic spleen cells on the proliferation of day 10 CFU-S and their entry into the cell cycle. This was done by comparing the number of day 10 CFU-S present in suspensions of normal bone marrow cells incubated for 2 days on agar underlays containing cells from either normal or neoplastic spleens. Our results show the existence of an activity secreted by cells from the spleens of MPSV-infected animals which starts CFU-S cycling and which is physically distinct from MPSV. The presence of this activity, whose identity with MPA remains to be proven, would enable us to explain the proliferation of CFU-S in the course of the disease.

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PubMed1985

Study of the 78A1 isolate of Moloney murine sarcoma virus. II. Haematopoietic tropism and tumourigenicity.

A new isolate of Moloney murine sarcoma virus (Mo-MuSV), designated 78A1, has been molecularly cloned. The cloned genome, found to be larger than that of other known isolates of the same virus is close in size to that of the myeloproliferative sarcoma virus (MPSV), also a derivative of the original Mo-MuSV/Moloney murine leukaemia virus (Mo-MuLV) complex. Until now, MPSV was the only Mo-MuSV isolate known to be capable of inducing a myeloproliferative disease associated with a tumoural syndrome when injected intravenously into sensitive mice. We compared the biological activity of our cloned virus isolate (78A1) and that of another cloned Mo-MuSV virus (HT1) whose genome is slightly smaller than that of 78A1. The helper virus (Mo-MuLV) associated with the Mo-MuSV isolates was also injected alone as control. After injection into sensitive mice only the isolate 78A1, as well as MPSV caused a tumoural syndrome invading spleen, liver and other haematopoietic organs, and the appearance of granulo-macrophage precursors not requiring exogenous stimulating factors for their proliferation and differentiation. The 78A1 virus has a longer latency period (3 months) than MPSV (several days) and does not induce a typical myeloproliferative disease.

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PubMed1984

Molecular cloning and characterization of a leukemia-inducing myeloproliferative sarcoma virus and two of its temperature-sensitive mutants.

The myeloproliferative sarcoma virus (MPSV) induces extensive hematopoietic changes, including spleen foci in adult mice, and transforms fibroblasts in vitro. NRK nonproducer cell lines of MPSV and ts temperature-sensitive mutants were analyzed by restriction enzyme digestion and Southern blotting. EcoRI fragments containing the proviral DNAs of MPSV and two temperature-sensitive mutants and rat cellular sequences homologous to c-mos were molecularly cloned. By comparing restriction enzyme cleavage sites, it was shown that the MPSV genome consists only of sequences related either to Moloney murine leukemia virus or to the c-mos mouse oncogenic sequences. Two regions of fragment heterogeneity were observed: (i) in the defective pol gene, where MPSV and the two cloned temperature-sensitive mutants were different from Moloney murine sarcoma virus and from each other, although MPSV wild-type retained more of the pol gene than any of the Moloney murine sarcoma virus isolates; (ii) in the area 3' to the mos gene, which was identical in MPSV and its temperature-sensitive mutants but different from other Moloney murine sarcoma virus variants. Transfection of cloned MPSV DNA in RAT4 cells and virus rescue on infection with Friend murine leukemia virus yielded MPSV which transformed fibroblasts in vitro and also induced spleen foci in adult mice, thus proving that both properties are coded by the same viral genome.

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PubMed1983

Myeloproliferative Sarcoma Virus stimulates pluripotent hematopoietic stem cells and provokes tumoral transformation of the hematopoietic microenvironment in vitro.

The Myeloproliferative Sarcoma Virus (MPSV) induces an increase in the number and concentration of pluripotent stem cells in long-term murine bone marrow cultures. This is followed by an increased number of precursor cells of the granulocyte and macrophage lines (GM-CFC). This increase is comparable to that observed in DBA/2 mouse spleens in vivo two to three weeks after viral infection. Proliferation of CFUs and GM-CFC decreases five weeks after infection with MPSV, in parallel to the gradual decline of reverse transcriptase activity in the culture medium. GM-CFC which can proliferate in the absence of added colony stimulating factor (CSF) were detected at week 6 post MPSV infection. Adherent tumor cells were observed nine weeks after infection. These fibroblast type cells gave rise to a permanent line which produced a CSF-like activity. Our results show that MPSV causes the tumoral transformation of fibroblast-like cells of the bone-marrow hematopoietic microenvironment. In addition, MPSV also strongly stimulates the proliferation of hematopoietic stem cells. MPSV is, until now, the first murine retrovirus which exhibits such properties.

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PubMed1983

Myeloproliferative syndrome induced by MPSV in DBA/2 mice: presence of a mixed-colonies promoting activity (MPA) in the spleen.

The myeloproliferative syndrome induced by the myeloproliferative sarcoma virus (MPSV) in DBA/2 mice stimulates the proliferation of pluripotent hemopoietic stem cells (HSC) and of progenitors committed toward granulomacrophagic and erythroid cell lines. This stimulation may result from a direct effect of the MPSV on HSC or from an indirect effect via locally secreted factors. Normal isogenic bone marrow cells were incubated in the mixed colony-forming unit system in semisolid medium supplemented with conditioned media obtained after incubating neoplastic spleen cells for 3 days at 37 degrees C. These spleen conditioned media contain an activity that is physically separable from MPSV by ultracentrifugation and which, in the presence of a very low quantity of erythropoietin, can induce in vitro the proliferation and differentiation of pluripotent HSC, detected by this Mix-CFU technique. We termed this activity mixed-colonies promoting activity (MPA). These results suggest that the hyperplasia of the nonlymphoid hematopoietic system in the neoplastic spleen results from an indirect effect of the MPSV on pluripotent HSC via locally secreted factors.

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PubMed1983

Hematopoietic precursors in disease induced by the myeloproliferative sarcoma virus.

Granulocyte and macrophage precursors (GM-CFU-C-), which differentiate in vitro without added granulocyte and macrophage colony stimulating factor (GM-CSF), can be detected in the hematopoietic organs of mice infected with myeloproliferative sarcoma virus (MPSV). Retransplantation experiments have shown that the GM-CFU-C- are incapable of autonomous growth and depend on a factor present in medium conditioned by MPSV spleen cells (MPSV-CM). This factor is not MPSV and is not produced by spleen cells of noninfected mice. Two classical sources of GM-CSF, lung GM-CSF and GM-CSF contained in the plasma of endotoxin-treated mice, cannot replace the MPSV factor. Inversely, MPSV-CM does not stimulate the growth of retransplanted clusters induced in normal bone marrow with lung GM-CSF, whereas lung GM-CSF does. Two conditioned media containing activity promoting the in vitro proliferation and differentiation of hematopoietic stem cells in the mixed colony assay stimulate the growth of MPSV clusters: one medium was conditioned by pokeweed-mitogen-stimulated spleen cells, the other by the WEHI 3 cell line. The implication of the results in the comprehension of MPSV disease is discussed.

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PubMed1982

Cellular proliferation kinetics of the murine sarcoma induced by the Moloney sarcoma virus.

Cell proliferation kinetics of the sarcoma induced by Moloney virus was studied in newborn Swiss OF1 mice. After in vivo injection of tritiated thymidine, followed by autoradiography, it was shown that the majority of cells were actively proliferating (labelling index; 31%, growth fraction 78%). The mean cell cycle was 16 hr and cell loss was relatively low (cell loss factor 48%). The study of tumour specific activity with time after a single [in vivo] injection of [3H]dR or [125I]UdR did not demonstrate the same degree of cell loss as that calculated by autoradiography. This result is consistent with a massive reutilization of radioactivity released by normal tissues.

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PubMed1982

A study of added GM-CSF independent granulocyte and macrophage precursors in mouse spleen infected with myeloproliferative sarcoma virus (MPSV).

A subpopulation of granulocyte and macrophage precursors (GM-CFUc) differentiating in the agar colony technique of Bradley and Metcalf into mature granulocytes and macrophages, without the addition of granulocyte and macrophage colony stimulating factor (GM-CSF), can be detected in MPSV infected mice. These precursors were detected 5 days after virus infection, reaching a maximal concentration of 1/10,000 spleen or bone marrow cells, 25 days after viral infection. The number of the added GM-CSF independent GM-CFUc was linearly correlated with the number of seeded MPSV hematopoietic cells. No GM-CSF producing cells could be detected in the MPSV spleen using normal bone marrow GM-CFUc as responder cells. Study of the GM-CSF sensitivity of the GM precursors has demonstrated the existence of two GM-CFUc populations in the MPSV spleen: a) a GM-CSF dependent population with a GM-CSF sensitivity similar to that of normal GM-CFUc b) a GM-CFUc population which differentiated in the absence of detectable amount of GM-CSF and of which differentiation was not affected by the addition of progressive amounts of GM-CSF. A possible model explaining these results is proposed.

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PubMed1981

Inheritance of susceptibility to the myeloproliferative sarcoma virus: effect of the Fv-2 locus and evidence for a myeloproliferative sarcoma virus resistance locus.

Myeloproliferative sarcoma virus (MPSV) causes a generalized stem cell leukemia with erythroid and myeloid hyperplasia in adult mice. MPSV also transforms fibroblasts. Mice congenic for the Fv-2 locus showed marked differences in susceptibility to MPSV according to the Fv-2 genotype. MPSV was injected into C57BL/6 Fvs and C57BL/6 Fv-2r mice congenic except for the Fv-2 locus. C57BL/6 mice with the Fvs genotype were much more susceptible to MPSV than were those with the Fvr genotype. Both DDD Fv-2r mice congenic with DDD Fv-2s mice except for the Fv-2 locus and DDD Fv-2s mice, however, were sensitive to spleen focus formation by MPSV. These data indicate that at least one additional resistance locus to MPSV is present in C57BL/6 mice but not in DDD mice. Both the Fv-2 locus and the putative MSPV resistance locus (loci) Mpsvr appear to be epistatic to either of the sensitivity loci. Fibroblast focus formation by MPSV was obtained well in C57BL/6 Fv-2r and C57BL/6 Fvs fibroblasts, indicating that the genes for MPSV resistance (Fv-2r and Mpsvr) were not operating in fibroblast cells. A model is proposed which may account for the differences in response of genetically different mice to MPSV and Friend spleen focus-forming virus.

Alleles↗
PubMed1981

Analysis of the myeloproliferative sarcoma virus genome: limited changes in the prototype lead to altered target cell specificity.

The myeloproliferative sarcoma virus (MPSV) derived from Moloney sarcoma virus (MSV-Mol) is a unique sarcoma virus which causes expansion of the hematopoietic stem cell compartment as well as the erythroid and myeloid cell lineages. MPSV also induces spleen focus formation in adult mice as do Friend and Rauscher viruses. Analysis of the MPSV genome on methyl mercury gels showed that the genome size is 7.0 kilobases, which is larger than the defective genome of any known MSV-Mol isolate. Hybridization analysis with specific cDNA probes showed that MPSV is a modified sarcoma virus with no sequences in the unique region of the defective sarcoma genome related to unique Friend virus sequences. The only viral sequences in the defective genome other than helper virus-related sequences are derived from the Moloney sarcoma virus genome with no new cellular sequences added. There was no evidence for induction of xenotropic virus sequences in MPSV-infected spleens of DBA/2J mice, indicating that spleen focus formation can be obtained by different mechanisms.

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PubMed1981

Cellular proliferation in the spleen of DBA/2 mice infected with a myeloproliferative sarcoma virus(MPSV).

Cellular proliferation kinetics were investigated in the spleens of DBA/2 mice infected with a myeloproliferative sarcoma virus (MPSV) at three distinct phases of spleen growth: the rapid-growth phase, the slow-growth phase and the regression phase. Using injection of tritiated thymidine in vivo and autoradiographic techniques, we showed that most blast cells proliferate rapidly (cell cycle is equal to 10 h) even during the slow-growth phase. Very massive and rapid cell loss was found during the rapid-growth phase (cell loss factor phi = 80%). By comparing the decrease in specific splenic activity after in vivo injection of 125IUdR and 3HTdR, we were able to show a large reutilization of tritiated thymidine (R = 57%), visible less than 7 h after injection of isotopic DNA precursors. Thus, MPSV-infected spleen cells were shown, for the most part, to be short-lived cells: almost one-half mature into erythrocytes and the others rapidly die in situ.

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PubMed1981

Myeloproliferative sarcoma virus (MPSV), a new tool for the study of hematopoiesis.

MPSV induces a myeloproliferative syndrome in susceptible mice associated with an invasion of hematopoietic and nonhematopoietic organs with tumor nodules. The effect of the virus on the various hematopoietic precursors (CFU-S, CFU-C, CFU-E, BFU-E) was studied in vivo in the spleen, blood, and bone marrow, and in vitro, using colony assays in semisolid medium. After in vivo and in vitro infection MPSV induces the appearance of CFU-C, independent of added colony-stimulating activity and of pure and mixed BFU-E, independent of burst-promoting activity. MPSV also induces in vivo an amplification of the size and concentration of the hematopoietic system, including hematopoietic stem cells. MPSV infection may also alter the hemapoietic microenvironment. Modification of the disease by total body irradiation followed by bone marrow stem cell reconstitution or by splenectomy is compatible with mediation of the virus effect at the level of hematopoietic microenvironment. MPSV may constitute a new tool to study the regulation of murine hematopoiesis and viral genetic information, which can specifically induce characteristic disturbances of this system.

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