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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of mice with Friend spleen focus-forming virus (SFFV) results in a multistage erythroleukemia. In the first stage, the SFFV envelope glycoprotein interacts with the erythropoietin receptor and a short form of the receptor tyrosine kinase sf-Stk, resulting in constitutive activation of signal transducing molecules and the development of erythropoietin (Epo)-independent erythroid hyperplasia and polycythemia. The second stage results from the outgrowth of a rare virus-infected erythroid cell that expresses nonphysiological levels of the myeloid transcription factor PU.1. These cells exhibit a differentiation block and can be grown as murine erythroleukemia (MEL) cell lines. In this study, we examined SFFV MEL cells to determine whether their transformed phenotype was associated with a block in the activation of any Epo signal-transducing molecules. Our studies indicate that Epo- or SFFV-induced activation of STAT1/3 DNA binding activity is blocked in SFFV MEL cells. The block is at the level of tyrosine phosphorylation of STAT1, although Jak2 phosphorylation is not blocked in these cells. In contrast to Epo, alpha interferon can induce STAT1 phosphorylation and DNA binding in SFFV MEL cells. The SFFV-transformed cells were shown to express elevated levels of the hematopoietic phosphatase SHP-1, and treatment of the cells with a phosphatase inhibitor restored STAT1 tyrosine phosphorylation. MEL cells derived from Friend murine leukemia virus (MuLV) or ME26 MuLV-infected mice, which do not express PU.1, express lower levels of SHP-1 and are not blocked in STAT1/3 DNA-binding activity. Our studies suggest that SFFV-infected erythroid cells become transformed when differentiation signals activated by STAT1/3 are blocked due to high SHP-1 levels induced by inappropriate expression of the PU.1 protein.
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PMID:Erythroblast transformation by the friend spleen focus-forming virus is associated with a block in erythropoietin-induced STAT1 phosphorylation and DNA binding and correlates with high expression of the hematopoietic phosphatase SHP-1. 1673 6

Various hematological abnormalities have been reported among neonates with Down syndrome. Thrombocytosis, thrombocytopenia, polycythemia, neutrophilia, transient myeloproliferative disorder (TMD), and congenital leukemia have all been reported. The two largest case series previously reported involved 63 and 31 cases. To acquire hematological data from a larger case series, we obtained all CBCs done during the first week after birth on all neonates with Down syndrome cared for in an Intermountain Healthcare (IHC) hospital with a date of birth between January 1, 2001 and December 31, 2005. During this period, 145,522 live births were recorded at 18 hospitals. Down syndrome was recognized in 226 (1 in 644). One hundred fifty-eight (70%) of these had one or more CBCs obtained before the seventh day (144 hr). Neonates who did versus did not have a CBC in the first week had a similar gestational age, birth weight, percentage who were LGA and SGA, and length of stay. Neutrophilia was the most common hematological abnormality detected, with 80% of absolute neutrophil counts above the upper limit of normal for age. Six percent (9/158) had blasts identified on the blood film and three, where this was persistent, were referred to the pediatric hematology service for further evaluation. The next most commonly detected abnormality was thrombocytopenia, with 66% of platelet counts <150,000/microl, and with 6% of counts <50,000/microl. The mean platelet volume did not correlate with the platelet count, but tended to run slightly large (9.2 +/- 1.3 fl), with 24% of values above 10 fl. Only one had a platelet transfusion. Polycythemia was the next most common hematological abnormality detected, with 33% of hematocrit values above 65% or hemoglobin concentrations above 22 g/dl. Six had a reduction transfusion. One patient had significant anemia (hematocrit <15%) and received an erythrocyte transfusion. One had neutropenia associated with an infection after bowel surgery. Neutrophilia, thrombocytopenia, and polycythemia were the most common hematological abnormalities observed among neonates with Down syndrome. Anemia, thrombocytosis, and neutropenia were not more common than among neonates who do not have Down syndrome. Hematological abnormalities were so common in this group that it seems reasonable to recommend that one or more CBCs be obtained on all neonates with Down syndrome.
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PMID:Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system. 1716 22

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
Leukemia 2008 Jan
PMID:Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. 1803 15

The approach to a patient with erythrocytosis is greatly simplified by assessing the clonality of the process upfront. In this regard, there has been a dramatic shift toward genetic testing and away from traditional tests, such as measurement of red cell mass. Clonal erythrocytosis is the diagnostic feature of polycythemia vera (PV) and is almost always associated with a JAK2 mutation (JAK2V617F or exon 12). All other scenarios represent non-clonal erythrocytosis, often referred to as secondary erythrocytosis. Serum erythropoietin (Epo) level is usually normal or elevated in secondary erythrocytosis and subnormal in PV. Therefore, in a patient with acquired erythrocytosis, it is reasonable to begin the diagnostic work-up with peripheral blood JAK2 mutation analysis and serum Epo measurement to distinguish PV from secondary erythrocytosis. Conversely, the patient with life-long erythrocytosis is more likely to suffer from congenital polycythemia and should therefore be evaluated for germline mutations that result in enhanced Epo effect (for example, Epo receptor mutations), altered intracellular oxygen sensing (for example, mutations involving the von Hippel-Lindau tumor suppressor gene) or decreased P50 (for example, high-oxygen-affinity hemoglobinopathy). The order of tests in this instance depends on the clinical scenario and serum Epo level.
Leukemia 2009 May
PMID:The complete evaluation of erythrocytosis: congenital and acquired. 1929 44

Polycythemia vera (PV) is a myeloproliferative disorder characterized by a pronounced increase in the number of erythroid cells. However, despite this aberrant proliferation, the incidence of erythroleukemia is paradoxically rare in PV patients. In this study, we show that the progression of Friend virus-induced erythroleukemia is delayed in a mouse model of primary familial congenital polycythemia in which the wild-type Epo-receptor (EpoR) gene is replaced with a truncated human EPOR gene. Herein, we show that these mice exhibit enrichment of Sca1(+)/cKit(-) progenitors and several mature immune cells, such as dendritic cells and macrophages. In cotransplantation experiments, Sca1(+)/cKit(-) progenitors inhibit the tumorigenicity of Sca1(-)/cKit(+) erythroleukemic cells. A cell line established from Sca1(+)/cKit(-) progenitors is also capable of inhibiting leukemic proliferation in culture and in mice. This phenomenon of leukemic inhibition, also detected in the serum of PV patients, is partially attributed to increased nitric oxide secretion. In addition, the administration of erythropoietin into leukemic mice induces a polycythemia-like state associated with the expansion of Sca1(+)/cKit(-) progenitors and derivative immune cells, thereby inhibiting leukemia progression. This study indicates that a combination therapy incorporating the enrichment of Sca1(+)/cKit(-) progenitors may serve as a novel approach for the treatment of leukemia.
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PMID:Enrichment of Sca1+ hematopoietic progenitors in polycythemic mice inhibits leukemogenesis. 1958 1

Radio iron is a tool which makes iron absorption studies quite accurate in dogs and reasonably satisfactory in human beings. This method is vastly superior to others previously used. Normal human pregnancy without significant anemia may show active radio iron absorption-16 to 27 per cent of iron intake. The pregnant woman as a rule shows 2 to 10 times the normal absorption of radio iron. Diseased states in which iron stores are known to be very abundant-pernicious anemia, hemochromatosis, familial icterus, and Mediterranean anemia -show very little absorption, probably less than normal. This is in spite of a severe anemia in all conditions except hemochromatosis. Chronic infections in spite of anemia show no utilization of radio iron, whether it may be absorbed or not. Leukemia shows little utilization of radio iron in red cells in spite of absorption (autopsy), probably because of white cells choking the red marrow. Polycythemia shows very low values for iron absorption as do normal persons. Two pregnant women showed only normal iron absorption. We believe that reserve stores of iron in the body, rather than anemia, control iron absorption. This control is exerted upon the gastro-intestinal mucosa which can refuse or accept iron under various conditions.
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PMID:RADIOACTIVE IRON ABSORPTION IN CLINICAL CONDITIONS: NORMAL, PREGNANCY, ANEMIA, AND HEMOCHROMATOSIS. 1987 Dec 18

Human liver tissue has been assayed to determine the amount of hemoglobin production factors in normal and abnormal states. Standardized dogs made anemic by blood removal have been used in this biological assay. Normal animal liver as control is rated as 100 per cent. Normal human liver tissue as compared with the normal animal control contains more of these hemoglobin production factors-a biological assay ratio of 120 to 160 per cent. Infections, acute and chronic, do not appear to modify these values, the concentration of hemoglobin-producing factors falling within the normal range. Pernicious anemia and aplastic anemia both show large liver stores of hemoglobin-producing factors-a biological assay ratio of 200 to 240 per cent. Therapy in pernicious anemia reduces these liver stores as new red cells are formed. Secondary anemia presents a low normal or subnormal liver store of hemoglobin-producing factors-an assay of 60 to 130 per cent. Hemochromatosis, erythroblastic anemia, and hemolytic icterus in spite of large iron deposits in the liver usually show a biological assay which is normal or close to normal. Polycythemia shows low reserve stores of hemoglobin-producing factors. Leukemias present a wide range of values discussed above. Hypoproteinemia almost always is associated with low reserve stores of hemoglobin-producing factors in the liver-biological assays of 60 to 80 per cent. Hypoproteinemia means a depletion of body protein reserve stores including the labile protein liver reserves-a strong indication that the prehemoglobin material (or globin) is related to these liver stores. Pregnancy, eclampsia, and lactation all may present subnormal liver stores of hemoglobin-producing factors. Exhaustion of protein stores lowers the barrier to infection and renders the liver very susceptible to many toxic substances. It should not be difficult to correct hypoproteinemia under these conditions and thus relieve the patient of a real hazard.
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PMID:HEMOGLOBIN PRODUCTION FACTORS IN THE HUMAN LIVER : ANEMIAS, HYPOPROTEINEMIA, CIRRHOSIS, PIGMENT ABNORMALITIES, AND PREGANCY. 1987 Dec 36

The diagnostic approach to a patient with polycythemia has been greatly simplified by the introduction of new genetic testing in addition to traditional tests, such as measurement of red cell mass and serum erythropoietin (Epo) level. Clonal erythrocytosis, which is the diagnostic feature of polycythemia vera (PV), is almost always associated with a JAK2 mutation (JAK2V617F or exon 12). Therefore, in a patient with acquired erythrocytosis, it is reasonable to begin the diagnostic work-up with JAK2 mutation analysis to distinguish PV from secondary erythrocytosis. The clinical course of PV is marked by a high incidence of thrombotic complications that represent the main cause of morbidity and mortality in these patients. Blood hyperviscosity as well as platelet and leukocyte quantitative, and qualitative abnormalities play a major role in the pathogenesis of thrombophilia. Prevention of vascular events and minimizing the risk of disease transition into acute leukaemia are the main targets of the whole PV treatment strategy. This can rely on the use of low-dose aspirin in most patients, while the choice of the optimal cytoreductive strategy is based on the individual vascular risk. Phlebotomy is still the preferred treatment in subjects at low risk, while hydroxyurea or pipobroman is usually administered to most elderly subjects or subjects with a previous vascular history. The use of pegylated interferon, imatinib, and JAK2 inhibitors is currently being evaluated.
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PMID:Polycythemia vera. 2082 16

Constitutional trisomy 21 inherent to Down syndrome (DS) is associated with several hematological disorders occurring at different ages. Neonates with DS may present with transient asymptomatic blood count abnormalities such as neutrophilia, thrombocytopenia and polycythemia. Within 1-2 months of life, 3-10% of DS infants develop transient myeloproliferative disease. Despite a spontaneous regression in most of the cases, TMD can be fatal or lead to the subsequent development of myeloid leukemia in 20% of DS children (DS ML). DS ML has clinical and biological features that define a unique entity with a high sensitivity to chemotherapy and a favorable outcome. Children with DS also have an increased risk of developing acute lymphoblastic leukemia (ALL) characterized by a more heterogeneous pattern of genetic findings and by a higher rate of treatment-related toxicities. These features highlight the role of trisomy 21 in leukemogenesis and confirm the need of specific and adapted therapeutic approach for DS children with leukemia.
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PMID:Hematological disorders and leukemia in children with Down syndrome. 2211 27

STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs.
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PMID:Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. 2250 49


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