Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Background: Hairy cell leukemia (HCL) is a slowly progressive lymphoproliferative disorder that tends to afflict middle-aged adults, especially men. Blastic transformation of this form of leukemia is extremely rare. To date, a single case has been reported. Methods and Results: A case of HCL, evolving with blastic transformation after a 9- year clinical course, is reported. Routine histology, cytochemistry, flow cytometry immunophenotyping, and Southern blot analysis for B- and T-cell gene rearrangements were used in the evaluation. Although morphology at the time of presentation was characteristic of HCL, the cells were initially tartrate-resistant acid phosphatase (TRAP) negative. During a clinical course over several years, the hairy cells became progressively TRAP positive. The morphology of the leukemic cells changed 9 years after initial diagnosis, with blastic transformation and retaining strong TRAP positivity. Immunophenotypic analysis showed evolution from a characteristic hairy cell leukemic phenotype to a phenotype indicative of marked immaturity. Genotypic analysis showed an evolving pattern of immunoglobulin gene rearrangements, paralleling the morphology and phenotypic evolution and ruling out a second B-cell malignancy. Conclusions: This case report of blastic transformation in a patient with HCL is only the second such case identified in the medical literature to date.
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PMID:Blastic Transformation in a Case of Hairy Cell Leukemia. 1008 74

The development of secure diagnostic immunoassays requires, among others, rigorous characterisation of potential antibody reagents. The reactivity profiles of seven antibodies (six monoclonal [MAb] and one polyclonal [PAb]) with putative specificity for tartrate-resistant acid phosphatase (TRAP) and/or osteoclasts were evaluated in enzyme-linked immunosorbent assay (ELISA) and/or immunocytochemistry. MAbs 2H1, 4E6 and 5Cl demonstrated assay restriction: exhibiting reactivity only in ELISA. The remaining three MAbs (G211D, G312G and V35B) and the PAb 8023 recognised recombinant TRAP (rTRAP) in ELISA and native acid phosphatases in selected tissues and cell lines. The latter were cytochemically assessed for both tartrate-sensitive acid phosphatase (TSAP) and TRAP. V35B showed reactivity against the monocytic leukaemia cell line U937 and guinea pig kidney tissue (both TSAP+ and TRAP+) and ECV304 (TSAP+) cells. Interestingly, the reactivity of MAb G211D co-localised with TRAP activity in the membrane of osteoclasts but also detected cytoplasmic components in U937 cells and human embryonic lung fibroblasts (TRAP+ and TRAP+). G211D exhibited immunoreactivity against placental trophoblasts (positive for total AP). Intriguingly, MAbs 2H1, 4E6, 5Cl and PAb 8023 cross-reacted with potato acid phosphatase in ELISA, suggesting reactivity to conformationally similar epitopes. Thus, some of these reagents could be used in the development of standardised diagnostic immunoassays or as drug-targeting agents for conditions in which the pathological process involves bone resorption, the MAbs G211D, 2H1, 4E6, 5Cl and PAb 8023 being useful in ELISA but not immunocytochemical detection of TRAP.
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PMID:Reactivity and assay restriction profiles of monoclonal and polyclonal antibodies to acid phosphatases: a preliminary study. 1065 66

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
Leukemia 2004 Aug
PMID:Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. 1521 75

The coexistence of hairy cell leukemia (HCL) and non-Hodgkin's lymphoma is extremely rare. In the few reports demonstrating such coexistence, the relationship between the 2 entities was mostly inconclusive. We report a case of HCL that transformed to large cell lymphoma. This case has been followed for more than 4 years with immunohistochemical, flow cytometric, and molecular genetic studies on multiple bone marrow biopsy specimens, a splenectomy specimen, and a lymph node biopsy. In our case, the immunophenotype and tartrate-resistant acid phosphatase stain confirmed that the large cell lymphoma was of HCL origin. The markedly increased Ki-67 staining (proliferation fraction) in the lymph node biopsy specimen compared to the earlier splenectomy specimen indicated the transformation of a low-grade leukemia to a high-grade lymphoma. The overexpression of p53 in the lymph node implies that p53 mutation was probably involved in the pathogenesis of HCL transformation.
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PMID:Transformation of hairy cell leukemia to high-grade lymphoma: a case report and review of the literature. 1566 2

Osteoclasts play a seminal role in many skeletal diseases and therefore are candidates for cell-based gene delivery systems to treat disorders of bone. As an initial step toward developing osteoclast-mediated gene delivery systems, we have made and analyzed a customized Molony-Murine leukemia virus (MMLV)-based retroviral vector containing elements of the osteoclast-specific tartrate-resistant acid phosphatase (TRAP) gene. RAW 264.7 cells were transduced with the customized vector (E3) and differentiated along macrophage or osteoclast lineages. E3 contained a truncated form of the human nerve growth factor receptor (NGFR) as a reporter gene. NGFR expression increased with RANK-ligand (RANK-L) treatment but not with macrophage (gamma-IFN/LPS treatment) differentiation. Enhanced NGFR expression peaked 48 h after RANK-L treatment. Electrophoretic mobility shift assays (EMSA) analysis of the TRAP gene regulatory elements in E3 identified a single 27 bp DNA probe, which specifically bound protein from RANK-L-treated cells. DNA sequence revealed AP-1 binding sites, and analysis with mutant probes implied that the sites were functional. EMSA supershift analysis identified Fos protein interacting with the 27 bp probe. In summary, insertion of sequence -962 to -868 from the TRAP gene into the U3 region of the MMLV LTR confers RANK-L induced retroviral gene expression via Fos family protein interaction at AP-1 sites.
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PMID:A customized retroviral vector confers marker gene expression in osteoclast lineage cells. 1622 14

The body cavities are rarely involved in hairy cell leukaemia. Here we report a patient who had pancytopenia, hepatosplenomegaly, massive haemorrhagic ascites, pleural effusion at the left hemithorax and increased CA 125 serum level at the time of initial diagnosis. Laparoscopy showed multiple nodular white, opaque lesions on the omentum and on the parietal peritoneum. Laparoscopic biopsy of these lesions, and a bone marrow biopsy revealed a diffuse cellular infiltrate of tartrate-resistant acid phosphatase staining mononuclear cells. These mononuclear cells with irregular cytoplasmic protrusions were also found in the peripheral blood, in the ascites fluid and in the pleural effusion. The patient was treated with cladribine 0.1 mg/kg/day with continuous infusion for seven days. Three months after the treatment, the patient achieved a complete remission with normalisation of the peripheral blood count, bone marrow findings, CA 125 serum level, with no detectable ascites and/or pleural effusion.
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PMID:Hairy cell leukaemia presenting with ascites, pleural effusion and increased CA 125 serum level. 1821 64

A 72-year-old Japanese man presented with 43.1 x 10(9)/l hairy cells and apparent splenomegaly. The leukemia cells had unevenly distributed microvilli and round nuclei with dense chromatin and one or two clear nucleoli, lacked CD25 expression and were negative for tartrate-resistant acid phosphatase. The case was diagnosed as hairy cell leukemia variant (HCLv) and proved refractory to various chemotherapies, including cladribine, pentostatin, interferon-alpha, CHOP and rituximab. Because of the CD52 expression, we treated the patient with alemtuzumab. Pretreatment with 22.5 Gy to the spleen reduced the spleen size from 12 to 4 cm below the left costal margin, and the number of circulating leukemic cells decreased from 229.0 to 63.6 x 10(9)/l. Subsequent administration of 24.0 mg of alemtuzumab eliminated leukemic cells in the peripheral blood on day 12, and the spleen was not palpable after the administration of 54.0 mg of alemtuzumab. In vitro treatment with alemtuzumab confirmed the cytotoxic effect against the patient's leukemic cells in the presence of complement. This is the first report showing clinical effectiveness of splenic irradiation and alemtuzumab against refractory HCLv.
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PMID:Effective treatment of a refractory hairy cell leukemia variant with splenic pre-irradiation and alemtuzumab. 1825 14

Human mesenchymal stem cells (hMSCs) from bone marrow were genetically marked by using a murine leukaemia virus construct encoding enhanced green fluorescent protein (eGFP). The marked cells were either directly implanted into the tibialis anterior muscle or introduced into a variety of other tissue sites in immunocompromised mice (NOD/SCID and C.B-17 SCID/beige) to investigate their fates and differentiation potentials. It was observed that the hMSCs survived for up to 12 weeks and showed site-specific morphological phenotypes. hMSCs delivered by intravenous injection were found mainly in the lungs and were detected rarely in other organs. Histomorphometry showed that, after implantation of hMSCs into the tibialis anterior muscle juxtaskeletally, the areas of reactive host callus formation at 1 and 2 weeks and of ectopic human bone formation at 1 week were significantly increased compared with the control group. Expression of eGFP and human RUNX2, alkaline phosphatase, osteocalcin, osteopontin, and collagen type I mRNAs were detected in mice implanted with the labelled hMSCs but not in sham-treated samples. Active clearance of the reactive callus and ectopic calcified tissue by osteoclast-like tartrate-resistant acid phosphatase-positive cells was observed. We conclude that the eGFP-labelled hMSCs can survive and retain the potential to differentiate morphologically into a variety of apparent mesenchymal phenotypes in vivo. Absolute confirmation of differentiation capacity requires further study and is complicated by known possibilities of fusion of donor and host cells or limited transfer of genetic material. Nevertheless, the genetically marked hMSCs are shown to participate extensively in bone formation and turnover. Control of the host osteoclast/macrophage responses resulting in clearance of formed osteogenic tissue warrants further investigation to promote prolonged human osteogenesis in immunocompromised mice. Furthermore, any proposed general cytotherapeutic strategy for enhanced osteogenesis is likely to require supplementation of local bone-forming biological signals.
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PMID:Fates and osteogenic differentiation potential of human mesenchymal stem cells in immunocompromised mice. 1841 47

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
Leukemia 2008 Oct
PMID:Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. 1859 40

Transcription factors play a crucial role in regulating differentiation processes during human life and are important in disease. The basic helix-loop-helix transcription factors Tal1 and Lyl1 play a major role in the regulation of gene expression in the hematopoietic system and are involved in human leukemia. Tal2, which belongs to the same family of transcription factors as Tal1 and Lyl1, is also involved in human leukaemia. However, little is known regarding the expression and regulation of Tal2 in hematopoietic cells. Here we show that Tal2 is expressed in hematopoietic cells of the myeloid lineage. Interestingly, we found that usage of the Tal2 promoter is different in human and mouse cells. Two promoters, hP1 and hP2 drive Tal2 expression in human erythroleukemia K562 cells, however in mouse RAW cells only the mP1 promoter is used. Furthermore, we found that Tal2 expression is upregulated during oesteoclastogenesis. We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression. Strikingly, PU.1 binding to the P1 promoter is conserved between mouse and human, but PU.1 binding to P2 was only detected in human K562 cells. Additionally, we provide evidence that Tal2 influences the expression of the osteoclastic differentiation gene TRACP. These findings provide novel insight into the expression control of Tal2 in hematopoietic cells and reveal a function of Tal2 as a regulator of gene expression during osteoclast differentiation.
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PMID:The T-cell oncogene Tal2 Is a Target of PU.1 and upregulated during osteoclastogenesis. 2408 57


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