Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytogenetic and fluorescence in situ hybridization studies were successfully performed in 217 chronic lymphocytic leukemia (CLL). In all, 13 patients with 6q21 deletion were identified and characterized in comparison with 92 patients with 'favourable' karyotype (normal or 13q-), 69 cases with 'intermediate risk' (1-2 anomalies) and 43 cases with 'unfavourable' karyotype (complex, 11q- or 17p-). Six out of 13 cases with 6q- showed an excess of atypical lymphocytes, a finding confirmed at the histologic level; >20% CD38+ cells were seen in 5/6 cases. IGVH mutational status revealed >98% homology to the germline sequence in 4/10 cases. When compared with the 'favourable' group, patients with 6q- showed a higher white blood cell (WBC) count, frequent splenomegaly, atypical morphology, CD38+ and short time from diagnosis to first treatment and short survival. A higher median WBC count was found in the 6q- group vs the intermediate-risk group; survival was shorter in the unfavourable group. To ascertain if the 6q- anomaly was an independent factor predicting for an inferior outcome among those patients with 'favourable' cytogenetics, we performed an analysis of prognostic factors in 105 patients (92 'favourable' plus 13 with 6q-), showing that the 6q- chromosome maintained its prognostic significance at multivariate analysis (P=0.02) along with stage (P=0.01). We conclude that CLL with 6q- is characterized by a high incidence of atypical morphology, classical immunophenotype with CD38 positivity and intermediate incidence of IGVH somatic hypermutation. Clinicobiological features and outcome show that this cytogenetic subset of CLL should be allocated in an intermediate-risk category.
Leukemia 2004 Mar
PMID:Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis. 1471 87

Aggressive natural killer-cell leukemia (ANKL) is a rare form of large granular lymphocyte leukemia, which is characterized by a systemic proliferation of NK cells. The clinical features of 22 ANKL cases were analyzed. Hepatomegaly (64%), splenomegaly (55%) and lymphadenopathy (41%) were also frequently observed. Leukemic cells were identified as CD1-, CD2+, surface CD3-, CD4-, CD5-, CD7+, CD8+/-, CD10-, CD11b+/-, CD13-, CD16+, CD19-, CD20-, CD25-, CD33(-), CD34-, CD38+, CD56+, CD122+, HLA-DR+ and TCR-. Two of the 16 cases examined for CD57 were positive and three of the seven cases examined for cytoplasmic CD3. Epstein-Barr virus was detected in the tumor cells of 11 of the 13 cases examined. No common cytogenetic abnormalities were identified and 6q anomaly was detected in only one. Three of 13 patients treated with chemotherapy containing anthracycline/anthraquinone attained complete remission, in contrast to none of the eight who were treated with regimens without anthracycline. Although the overall prognosis was poor with a median survival of 58 days, those who attained remission showed better prognosis (P=0.005). These findings suggest that ANKL is an entity of mature cytotoxic NK-cell neoplasms with distinct phenotype and disease presentations. Intensive treatment for ANKL may result in a better prognosis.
Leukemia 2004 Apr
PMID:Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. 1496 Oct 41

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.
Leukemia 2004 Apr
PMID:Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. 1497 4

In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naive human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-beta2microglobulin-/- mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5-6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.
Leukemia 2005 Mar
PMID:BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice. 1567 17

T-cell large granular lymphocytes (LGL) proliferations range from reactive expansions of activated T cells to T-cell leukemias and show variable clinical presentation and disease course. The vast majority of T-LGL proliferations express TCRalphabeta. Much less is known about the characteristics and pathogenesis of TCRgammadelta+ cases. We evaluated 44 patients with clonal TCRgammadelta+ T-LGL proliferations with respect to clinical data, immunophenotype and TCR gene rearrangement pattern. TCRgammadelta+ T-LGL leukemia patients had similar clinical presentations as TCRalphabeta+ T-LGL leukemia patients. Their course was indolent and 61% of patients were symptomatic. The most common clinical manifestations were chronic cytopenias - neutropenia (48%), anemia (23%), thrombocytopenia (9%), pancytopenia (2%) - and to a lesser extent splenomegaly (18%). Also multiple associated autoimmune (34%) and hematological (14%) disorders were found. Leukemic LGLs were predominantly positive for CD2, CD5, CD7, CD8, and CD57, whereas variable expression was seen for CD16, CD56, CD11b, and CD11c. The Vgamma9/Vdelta2 immunophenotype was found in 48% of cases and 43% of cases was positive for Vdelta1, reflecting the TCR-spectrum of normal TCRgammadelta+ T-cells in adult PB. Identification of the well-defined post-thymic Vdelta2-Jdelta1 selection determinant in all evaluable Vgamma9+/Vdelta2+ patients, is suggestive of common (super)antigen involvement in the pathogenesis of these TCRgammadelta+ T-LGL leukemia patients.
Leukemia 2006 Mar
PMID:TCRgammadelta+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRgammadelta+ T-cells. 1643 45

We conducted the first nationwide survey to clarify the clinical features, treatment methods, and prognoses for polycythemia vera (PV) and essential thrombocythemia (ET). A 1-page questionnaire was mailed to members of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG). Surveys on 647 patients (PV, 266 patients; ET, 381 patients) were returned and analyzed. Thrombotic events at diagnosis and during follow-up occurred at rates of 15.4% and 8.5%, respectively, in PV cases and 17.6% and 8.7% in ET cases. Splenomegaly was observed in only 28.8% of PV patients and 10.8% of ET patients. The leukocyte alkaline phosphatase score was elevated in only 46.2% of PV patients. The incidences of abnormal karyotypes were less than 10% in both PV and ET cases. The rates of transformation to myelofibrosis were 2.6% in both PV and ET cases, and acute leukemia was noted in 1.1% of PV patients and 2.9% of ET patients. Prognostic factors were thrombotic history for PV and thrombotic history and age (>or=60 years) for ET. The present study clearly demonstrated clinical differences between Japanese and Western patients for PV and ET. Concerning the treatment of PV and ET, the study revealed considerable variation among Japanese hematologists. These results suggest the necessity of developing treatment guidelines according to risk stratification that are suitable for Japanese PV and ET patients.
 ...
PMID:Clinical features of polycythemia vera and essential thrombocythemia in Japan: retrospective analysis of a nationwide survey by the Japanese Elderly Leukemia and Lymphoma Study Group. 1678 77

Evidence is continuing to accumulate that the FMS-like tyrosine kinase 3 (FLT3) receptor plays an important role in acute leukemias. Acute myeloid leukemia patients often express constitutive active mutant forms of the receptor in their leukemic cells. A t(12;13)(p13;q12) translocation between Tel and the FLT3 receptor was recently described in a patient with myeloproliferative disease (MPD). Here a Tel-FLT3 construct mimicking this fusion protein was used to generate transgenic mice. The fusion protein was previously found to constitutively activate FLT3 signaling and transform Ba/F3 cells. Expression of the fusion protein in the transgenic mice was found in all tissues assayed including spleen, bone marrow (BM), thymus and liver. These mice developed splenomegaly and had a high incidence of MPD with extramedullary hematopoiesis in the liver and lymph nodes. Spleens also had increased dendritic and natural killer cell populations. In vitro analysis of the hematopoietic progenitor cells derived from Tel-FLT3 transgenic mice showed a significant increase in the number of CFU-GM in the BM, and CFU-GM, BFU-E and CFU-GEMM in the spleen. BM also showed significant increases of in vivo CFU-S colonies. Thus, transgenic mice expressing constitutively activated Tel-FLT3 develop MPD with a long latency and also result in the expansion of the hematopoietic stem/progenitor cells.
Leukemia 2007 Apr
PMID:Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease. 1726 28

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

Hairy cell Leukemia (HCL) is a chronic lymphoproliferative disorder that was characterized in the late 1950s. HCL is defined, according to the WHO classification, as a mature (peripheral) B-cell neoplasm (1). HCL accounts for between 2-3% of all leukemia cases, with about 600 new cases diagnosed in the U.S. each year (1). HCL occurs more commonly in males, with an overall male to female ratio of approximately 4:1. The median age of onset is 52 years. This disease is seen more commonly in Caucasians and appears to be especially frequent in Ashkenazi Jewish males, with rare occurrence in persons of Asian and African descents (1). Hairy cells are distinct, clonal B cells arrested at a late stage of maturation. They are small B lymphoid cells that possess oval nuclei and abundant cytoplasm with characteristic micro-filamentous ("hairy") projections. They strongly express CD103, CD22, and CD11c (2). These cells typically infiltrate the bone marrow, the spleen, and to a lesser extent the liver, lymph nodes, and skin. Many patients present with splenomegaly and pancytopenia. Other clinical manifestations include recurrent opportunistic infections and vasculitis. Historically, HCL was considered uniformly fatal (2). However, recent treatment advances, using purine analogues such as Cladribine and Pentostatin, led to a significant improvement in prognosis with achievement of high response rates and durable remissions (2).
 ...
PMID:Hairy cell leukemia: current concepts. 1879 68

Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-alpha2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-alpha in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-alpha induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-alpha the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-alpha on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-alpha in JAK2-mutated MPN.
Leukemia 2008 Nov
PMID:Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. 1884 85


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