Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.
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PMID:WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. 1785 29

Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.
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PMID:Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. 1795 57

CD200 is an immunosuppressive molecule overexpressed in multiple hematologic malignancies such as B cell chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia. We previously demonstrated that up-regulation of CD200 on tumor cells suppresses antitumor immune responses and that antagonistic anti-human CD200 mAbs enabled human PBMC-mediated tumor growth inhibition in xenograft NOD/SCID human (hu)-mouse models. Ab variants with effector function (IgG1 constant region (G1)) or without effector function (IgG2/G4 fusion constant region (G2G4)) exhibited high antitumor activity in a human tumor xenograft model in which CD200 was expressed. In this report, we seek to select the best candidate to move forward into the clinic and begin to decipher the mechanisms of tumor cell killing by comparing anti-CD200-G1 vs anti-CD200-G2G4 in two related animal models. In a CD200-expressing xenograft NOD/SCID hu-mouse model where CD200 ligand/receptor interactions are already established before initiating treatment, we find that anti-CD200-G1 is a less effective Ab compared with anti-CD200-G2G4. Separately, in a model that evaluates the effect of the Abs on the immune cell component of the xenograft NOD/SCID hu-mouse model distinctly from the effects of binding to CD200 on tumor cells, we find that the administration of anti-CD200-G1 Abs completely abolished human PBMC-mediated tumor growth inhibition. Along with supporting in vitro studies, our data indicate that anti-CD200-G1 Abs efficiently mediate Ab-dependent cellular cytotoxicity of activated T cells, critical cells involved in immune-mediated killing. These studies suggest important implications regarding the selection of the constant region in anti-CD200 immunotherapy of cancer patients.
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PMID:Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy. 1817 7

We investigated the effect of human bone marrow-derived mesenchymal stem cells on engraftment of human umbilical cord blood CD34+ cells and acute myelogenous leukemia cells and also assessed the homing capability of MSCs. Forty-two NOD/SCID mice were administered sublethal irradiation followed by various cell doses of intravenous UCB CD34+ cells with or without MSCs. Another 12 NOD/SCID mice were also sublethally irradiated followed by intravenous injection of AML cells with or without MSCs. In ten of these mice, MSCs were genetically modified with an adenoviral vector encoding eGFP gene for tracking purpose. Cotransplantation of UCB CD34+)cells and MSCs resulted in a significant increase in bone marrow engraftment after 6 weeks, and the engraftment promoting effect of MSCs was proportional to the dose of MSCs and obvious when low doses of UCB CD34+ cells were given. There was no effect of MSCs on AML cells engraftment. All of the ten mice transplanted with eGFP-transfected MSCs showed positive for eGFP in their major organs. These data demonstrate that MSCs promote engraftment of UCB CD34+ cells in bone marrow, but exert no effect on engraftment of AML cells, and are capable of homing to the major organs including bone marrow following intravenous infusion.
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PMID:Effect of mesenchymal stem cell transplantation on the engraftment of human hematopoietic stem cells and leukemic cells in mice model. 1829 59

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.
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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

Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
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PMID:Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells. 1866 Mar 79

Transplantation of human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) primary cells and cell lines in different strains of immunodeficient mice has led to preclinical models extensively used to investigate acute leukemia stem cells, biology and drug sensitivity. We studied the engraftment kinetics of AML and ALL cell lines and primary cells in 3 strains of NOD.CB17-Prkdc(scid) (NOD/scid, NS)-related mice (NOD.Cg-Prkdc(scid)B2m(tm1Unc)/J, abbreviated NOD/scid/beta2 null, NSB; and NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ, abbreviated NOD/scid/IL-2Rgamma null, NSG). The engraftment of human malignant cells was investigated by means of clinicopathological criteria, flow cytometry, PCR and immunohistochemistry. In NSG mice, we observed a significantly faster development of leukemia-related symptoms and a higher percentage of leukemia cells in the blood, in the marrow and in the spleen. The leukemia-related angiogenic switch (measured as the number of circulating endothelial cells and progenitors) was faster in NSG compared to NS and NSB mice. These models will be instrumental to studies on leukemia-initiating stem cells, leukemia biology, preclinical treatment studies, and to obtain patient-specific preclinical models to design and investigate patient-tailored therapies.
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PMID:Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. 1868 47

BH3-only members of the Bcl-2 family exert a fundamental role in apoptosis induction. This work focuses on the development of a novel peptidic molecule based on the BH3 domain of Bim. The antiapoptotic molecule Bcl-X(L), involved in cancer development/progression and tumour resistance to cytotoxic drugs, is a target for Bim. According to a rational study of the structural interactions between wt Bim-BH3 and Bcl-X(L), we replaced specific residues of Bim-BH3 with natural and non-natural aminoacids and added an internalizing sequence, thus increasing dramatically the inhibitory activity of our modified Bim-BH3 peptide, called 072RB. Confocal microscopy and flow cytometry demonstrated cellular uptake and internalization of 072RB, followed by co-localization with mitochondria. Multiparameter flow cytometry demonstrated that the 072RB dose-dependent growth inhibition of leukaemia cell lines was due to apoptotic cell death. No effect was observed when cells were treated with the internalizing vector alone or a mutated control peptide (single aminoacid substitution L94A). Ex-vivo derived leukemic cells from acute myeloid leukaemia (AML) patients underwent cell death when cultured in vitro in the presence of 072RB. Conversely, no significant cytotoxic effect was observed when 072RB was administered to cultures of peripheral blood mononuclear cells, either resting or PHA-stimulated, and bone marrow cells of normal donors. Xenografts of human AML cells in NOD/SCID mice displayed a significant delay of leukemic cell growth upon treatment with 072RB administered intravenously (15 mg/Kg three times, 48 hours after tumour cell injection). Altogether, these observations support the therapeutic potentials of this novel BH3 mimetic.
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PMID:A novel Bim-BH3-derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity. 1884 3

With the emergence of the concept of the leukemia stem cell, assays to study them remain pivotal in understanding (leukemic) stem cell biology. Although the in vivo NOD-SCID xenotransplantation model is still the favored model of choice in most cases, this system has some limitations as well, such as its cost-effectiveness, duration, and the lack of engraftability of cells from subsets of acute myeloid leukemia (AML) patients. Here, we have described an ex vivo bone marrow stromal coculture system in which CD34(+) cells, but not CD34(-) cells, from the bone marrow or peripheral blood of AML patients can give rise to long-term cultures (LTC) that can be maintained for over 20 weeks. Long-term expansion is associated with the formation of leukemic cobblestone area (L-CA) formation underneath the stroma. Self-renewal within these L-CAs can be determined by sequential passaging of these L-CAs onto new MS5 stromal layers, which results in the generation of second, third, and fourth L-CAs that are able to sustain long-term expansion and generate high numbers of immature undifferentiated suspension cells. Furthermore, we have optimized lentiviral transduction procedures in order to stably express genes of interest or stably downmodulate genes using RNAi in AML CD34(+) cells, and this method has also been described here. Together, these tools should allow a further molecular elucidation of derailed signal transduction in AML stem cells.
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PMID:Ex vivo assays to study self-renewal and long-term expansion of genetically modified primary human acute myeloid leukemia stem cells. 1927 87

Distinct leukemia-initiating cells (L-ICs) represent a critical target for therapeutic intervention of acute myeloid leukemia (AML). A potential strategy to eradicate L-ICs is to generate L-IC-specific cytotoxic T lymphocytes (CTLs). However, owing to rarity and immortality of L-ICs, it is difficult for antigen-presenting cells to capture L-ICs for specific antigen presentation. Here, we report a novel approach by fusing allogeneic dendritic cells (DCs) and CD34CD38 AML progenitor cells, through which specific CTLs were effectively induced, leading to the cytolysis to AML-initiating cells. Fusion of either DC/CD34CD38 AML cell or DC/CD34 AML cell could effectively induce the proliferation and activation of CTLs. However, only the former CTLs could effectively attack AML progenitor cells, and result in the unkilled progenitor/initiating cells losing the abilities of active proliferation in vitro and engraftment in NOD-SCID mice. These findings suggest that AML progenitor/initiating cell-specific CTLs may be generated based on allogeneic DC/progenitor cell fusion strategy; the induced CTLs may potentially eradicate AML by targeting L-ICs directly or indirectly.
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PMID:Fusion of dendritic cells and CD34+CD38- acute myeloid leukemia (AML) cells potentiates targeting AML-initiating cells by specific CTL induction. 1934 64


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