Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Internal tandem duplications of the FIt3 gene (FIt3/ITDs) are present in about 18% of all AML cases and are therefore one of the most frequent somatic gene mutations in AML. Little is known about the role of FIt3/ITDs in leukemogenesis or their clinical relevance. In this study we compared 18 samples with FIt3/ITDs and 63 AML samples without these mutations with respect to clinical prognosis, cytokine responsiveness, progenitor cell content and repopulation in the NOD/SCID mouse. We found that in patients with a mutation CR rates are reduced (P=0.03) and relapse rates are increased (P=0.01), indicating the prognostic importance of FIt3/ITDs. This is also emphasized by the finding that in patients under the age of 60 years, as well as in older patients the event-free survival was more unfavorable for the mutant patients (P=0.003 and P=0.03, respectively). At diagnosis FIt3/ITD and non-mutant AML bone marrow samples did not differ in their progenitor/stem cell frequencies. Cobblestone area forming cell (CAFC) subsets showed a similar frequency distribution in mutant and non-mutant samples. In 7-day liquid cultures, FIt3/ITD samples showed a reduced growth in response to a variety of myeloid growth factors. In contrast, FIt3/ITD samples displayed a higher ability to engraft the NOD/SCID bone marrow with leukemic cells. Together these data show that the FIt3/ITD represents an important diagnostic marker for patient prognosis, and that the presence of these mutations is associated with altered proliferative ability of progenitors in vivo and in vitro.
 ...
PMID:Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. 1076 54

Several studies point to multiple members of the Hox transcription factor family as playing key roles in normal hematopoietic development, and they link the imbalanced expression of these transcription factors, in particular of the Abd-like A cluster HOX genes HOXA9 and HOXA10, to leukemogenesis. To test directly the hypothesis that HOXA10 is involved in human hematopoietic development, the gene was retrovirally overexpressed in human highly purified CD34(+)/GFP(+) hematopoietic progenitor cells derived from cord blood or fetal liver sources, and the impact of aberrant gene expression was analyzed on differentiation and proliferation in vitro and in vivo. HOXA10 misexpression profoundly impaired myeloid differentiation with a higher yield of blast cells in liquid culture and a greater than 100-fold increased generation of blast colonies after in vitro expansion or after replating of primary colonies first plated in methylcellulose directly after transduction (P < .01). Furthermore, aberrant HOXA10 expression almost completely blocked erythroid differentiation in methylcellulose (P < .02). HOXA10 deregulation also severely perturbed the differentiation of human progenitors in vivo, reducing B-cell development by 70% in repopulated NOD/SCID mice and enhancing myelopoiesis in the transduced compartment. The data provide evidence that the balanced expression of HOXA10 is pivotal for normal human hematopoietic development and that aberrant expression of the gene contributes to impaired differentiation and increased proliferation of human hematopoietic progenitor cells. These results also provide a framework to initiate more detailed analyses of HOX regulatory domains and HOX cofactors in the human system in vitro and in vivo.
 ...
PMID:Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo. 1129 May 89

Ras proteins are frequently over-expressed in leukemia and contribute to leukemogenesis. We evaluated the anti-leukemic efficacy of a new third-generation bisphosphonate, ONO5920/YM529 (YM529). YM529 prevents the prenylation of Ras proteins and inhibited the growth of leukemic cells including a P-glycoprotein (P-gp) over-expressing cell line in a concentration- and time-dependent manner by inducing apoptosis in vitro. Moreover, YM529 synergistically augmented the anti-leukemic activities of paclitaxel and daunorubicin in vitro. Importantly, YM529 prolonged the survival of NOD/SCID mice engrafted with human primary leukemic cells. These findings indicate that the YM529 may become a novel molecular therapeutic class for treatment of leukemias.
 ...
PMID:The anti-leukemic efficacy of the third generation bisphosphonate ONO5920/YM529. 1572 80

The t(16:16) and inv(16) are associated with FAB M4Eo myeloid leukemias and result in fusion of the CBFB gene to the MYH11 gene (encoding smooth muscle myosin heavy chain [SMMHC]). Knockout of CBFbeta causes embryonic lethality due to lack of definitive hematopoiesis. Although knock-in of CBFB-MYH11 is not sufficient to cause disease, expression increases the incidence of leukemia when combined with cooperating events. Although mouse models are valuable tools in the study of leukemogenesis, little is known about the contribution of CBFbeta-SMMHC to human hematopoietic stem and progenitor cell self-renewal. We introduced the CBFbeta-MYH11 cDNA into human CD34+ cells via retroviral transduction. Transduced cells displayed an initial repression of progenitor activity but eventually dominated the culture, resulting in the proliferation of clonal populations for up to 7 months. Long-term cultures displayed a myelomonocytic morphology while retaining multilineage progenitor activity and engraftment in NOD/SCID-B2M-/- mice. Progenitor cells from long-term cultures showed altered expression of genes defining inv(16) identified in microarray studies of human patient samples. This system will be useful in examining the effects of CBFbeta-SMMHC on gene expression in the human preleukemic cell, in characterizing the effect of this oncogene on human stem cell biology, and in defining its contribution to the development of leukemia.
 ...
PMID:Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. 1667 Feb 69

Emerging reports are conclusively demonstrating the mutagenic risks involved in using retroviral vectors for gene therapy. Animal studies, as well as cases from a human clinical trial, have proven the potential of insertional leukemogenesis caused by a retroviral vector. Here, we report the observation of six T-lymphoblastic leukemia cases arising during the course of a gene therapy study for hemophilia B after transplantation of ex vivo transduced hematopoietic stem cells (HSCs) by a lentivirus vector. Three of these animals comprised secondary recipients of the same donor and LAM-PCR was performed to identify the vector integration loci. We located integrations in repeat elements of known genes, including a candidate brain-tumor locus, but none of these clones could be tracked in the leukemic blasts. Although transduced clones with an intact proviral cassette were detected in the spleen of the leukemic animals, they comprised a very small proportion, not correlating to the levels of leukemic blasts. After propagation of the latter in NOD/SCID mice, we could no longer detect the proviral cassette suggesting that the leukemic blasts were untransduced. We did, however, detect increased levels of reverse transcriptase activity in the leukemic blasts which may suggest activation of endogenous retroviruses. This study demonstrates that tumors arising in these type of gene therapy protocols are not necessarily due to vector insertional mutagenesis and highlights the importance of careful functional studies to delineate the nature of tumorigenesis.
 ...
PMID:Murine leukemia following irradiation conditioning for transplantation of lentivirally-modified hematopoietic stem cells. 1737 92

Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor kappaB (NF-kappaB). NF-kappaB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-kappaB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1 alpha expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.
 ...
PMID:A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. 1808 16

The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38-CD19+ and CD34+CD38-CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2rgamma(null) mice. We found that both CD34+CD38+CD19+ and CD34+CD38-CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38-CD10-CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38-CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2rgamma(null) recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.
 ...
PMID:CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. 1841 10

Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is dispensable for HTLV-1-mediated cellular transformation in cell culture, but is required for efficient viral infectivity and persistence in rabbits. In most adult T-cell leukemia (ATL) cells, Tax oncoprotein expression is typically low or undetectable, whereas Hbz gene expression is maintained, suggesting that Hbz expression may support infected cell survival and, ultimately, leukemogenesis. Emerging data indicate that HBZ protein can interact with cAMP response element binding protein (CREB) and Jun family members, altering transcription factor binding and transactivation of both viral and cellular promoters. Herein, lentiviral vectors that express Hbz-specific short hairpin (sh)-RNA effectively decreased both Hbz mRNA and HBZ protein expression in transduced HTLV-1-transformed SLB-1 T cells. Hbz knockdown correlated with a significant decrease in T-cell proliferation in culture. Both SLB-1 and SLB-1-Hbz knockdown cells engrafted into inoculated NOD/SCID(gammachain-/-) mice to form solid tumors that also infiltrated multiple tissues. However, tumor formation and organ infiltration were significantly decreased in animals challenged with SLB-1-Hbz knockdown cells. Our data indicate that Hbz expression enhances the proliferative capacity of HTLV-1-infected T cells, playing a critical role in cell survival and ultimately HTLV-1 tumorigenesis in the infected host.
 ...
PMID:Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. 1868 44

In this study, we tested if FLT3/internal tandem duplication (ITD) in acute myeloid leukemia (AML) might occur at different hierarchical stages during leukemogenesis. In 56 AML cases, 10 showed FLT3/ITD (single ITD=5; multiple ITD=5). Myeloblasts from seven cases (CD34-selected=4; unselected=3) were transplanted into NOD/SCID mice. Five cases engrafted successfully into 14 mice. Two patients carried single FLT3/ITD subclones, which were maintained during primary and secondary transplantations. In three patients with multiple FLT3/ITD subclones, some subclones persisted or expanded while others diminished upon transplantation. Their different engraftment capabilities in NOD/SCID mice supported the proposition that FLT3/ITD might occur at different stages during leukemogenesis.
 ...
PMID:FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice. 1968 12

The molecular and genetic factors induced by human T-lymphotropic virus type-1 (HTLV-1) that initiate adult T-cell leukemia/lymphoma (ATLL) remain unclear, in part from the lack of an animal model that accurately recapitulates leukemogenesis. HTLV-1-infected humanized nonobese diabetic severe combined immunodeficiency (HU-NOD/SCID) mice were generated by inoculation of NOD/SCID mice with CD34(+) hematopoietic progenitor and stem cells (CD34(+) HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice exclusively developed CD4(+) T-cell lymphomas with characteristics similar to ATLL and elevated proliferation of infected human stem cells (CD34(+)CD38(-)) in the bone marrow were observed in mice developing malignancies. Purified CD34(+) HP/HSCs from HTLV-1-infected patient peripheral blood mononuclear cells revealed proviral integrations suggesting viral infection of human bone marrow-derived stem cells. NOD/SCID mice reconstituted with CD34(+) HP/HSCs transduced with a lentivirus vector expressing the HTLV-1 oncoprotein (Tax1) also developed CD4(+) lymphomas. The recapitulation of a CD4(+) T-cell lymphoma in HU-NOD/SCID mice suggests that HSCs provide a viral reservoir in vivo and act as cellular targets for cell transformation in humans. This animal model of ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.
 ...
PMID:Adult T-cell leukemia/lymphoma development in HTLV-1-infected humanized SCID mice. 2491 10


1 2 3 Next >>