scholarly journals STAT3 Inhibition Enables TLR9-Driven Differentiation of Cbfb/Myh11 acute Myeloid Leukemia Cells to Antigen-Presenting Cell Phenotype In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4070-4070
Author(s):  
Marcin Kortylewski ◽  
Priyanka Duttagupta ◽  
Yu-Lin SU ◽  
Tomasz Adamus ◽  
Guido Marcucci
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Pharmacological Intervention ◽  
Cell Phenotype ◽  
Atp Production ◽  
Antigen Presenting ◽  
Stat3 Inhibition ◽  
Acute Myeloid

Abstract STAT3 transcription factor is persistently activated in cancer cells and in diverse tumor-associated immune cells being an important oncogene and an essential immune checkpoint regulator. It is a highly desirable but challenging therapeutic target for pharmacological intervention. We previously demonstrated that ligand for the intracellular receptor TLR9 (CpG oligonucleotide) allows for the uptake and cytoplasmic delivery of decoy oligodeoxynucleotides (dODNs) to inhibit transcriptional activity of STAT3 in a variety of human and mouse acute myeloid leukemia (AML) cells. Here, we demonstrate that CpG-STAT3dODN injected intravenously to mice engrafted with Cbfb/MYH11 AML, dramatically altered leukemic cell morphology, by reducing nucleus-cytoplasm ratio and increasing mitochondria size, and also resulting in metabolic shift from glycolysis to oxidative phosphorylation, resulting in increased mitochondrial ATP production. The transcriptional profiling of AML cells isolated from spleens of mice treated using CpG-STAT3dODN vs control CpG-scrODN or PBS, revealed the increased expression of genes regulating myeloid cell differentiation (Irf8, Cebpa, Gadd45a) and antigen-presentation (B2m, CIIta, IL-12a, Ifng), with decrease of leukemia-related regulators Runx1and Run1t1. Thein vivodifferentiation of leukemic cells was confirmed using flow cytometry by detecting appearance of the population of AML-derived CD11b+/MHCII+/CD86+myeloid cells after CpG-STAT3dODN but not control treatments. Furthermore, we confirmed that the differentiated AML cells have immunogenic effects, which drive expansion of Th1 effector T cell responses in Cbfb/MYH11 as well as C1498 AML models. Overall, our studies suggest that STAT3-inhibition can unleash immune-stimulatory potential downstream of TLR9 signaling transforming AMLcells into antigen-presenting cells. These findings support development of CpG-STAT3dODN strategy as a new bi-functional agent for AML immunotherapy. This project described was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA213131 to M.K. Disclosures Kortylewski: N/A: Patents & Royalties: I am an inventor on the US patent 9,976,147.

scholarly journals Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2404-2412 ◽  
Author(s):  
DC Roy ◽  
JD Griffin ◽  
M Belvin ◽  
WA Blattler ◽  
JM Lambert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Short Exposure ◽  
Continuous Exposure ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti- MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti- MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9- bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C′), Anti- MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU- GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.

In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4622-4628 ◽  
Author(s):  
Gunter Schuch ◽  
Marcelle Machluf ◽  
Georg Bartsch ◽  
Masashi Nomi ◽  
Henri Richard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor ◽  
Acute Myeloid

Recent findings implied that the progression of hematologic malignancies, like that of solid tumors, is dependent on neovascularization. Recent studies on patients with acute myeloid leukemia (AML) showed increased levels of leukocyte-associated vascular endothelial growth factor (VEGF) and neovascularization of the bone marrow. Murine (32D, M1) and human (HEL, U937, and UKE-1) leukemic cell lines and freshly isolated leukemic cells were analyzed for the expression of VEGF and VEGF receptor mRNA. The expression of VEGF and VEGF receptors KDR and neuropilin-1 (NRP-1) was detected in these cells. In a murine chloroma model, delivery of VEGF165using microencapsulation technology resulted in enhanced tumor growth and vascularization, whereas treatment with a VEGF antagonist soluble NRP-1 (sNRP-1) inhibited tumor angiogenesis and growth. In a systemic leukemia model, survival of mice injected with adenovirus (Ad) encoding for Fc-sNRP-1 (sNRP-1 dimer) was significantly prolonged as compared with mice injected with Ad-LacZ. Further analyses showed a reduction in circulating leukemic cells and infiltration of liver and spleen as well as bone marrow neovascularization and cellularity. Taken together, these results demonstrate that angiogenic factors such as VEGF promote AML progression in vivo. The use of VEGF antagonists as an antiangiogenesis approach offers a potential treatment for AML. Finally, our novel in vivo drug delivery model may be useful for testing the activities of other peptide antiangiogenic factors.

scholarly journals Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 1107-1117 ◽  
Author(s):  
Satomi Tanaka ◽  
Satoru Miyagi ◽  
Goro Sashida ◽  
Tetsuhiro Chiba ◽  
Jin Yuan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Fusion Gene ◽  
Hematologic Malignancies ◽  
Leukemic Cells ◽  
Polycomb Repressive Complex 2 ◽  
Acute Myeloid

Abstract EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2flox/flox mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia–like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.

scholarly journals Combination of BCL-2 Inhibition and Triptolide Causes Synthetic Lethality in Acute Myeloid Leukemia through Preventing Reciprocal Resistance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2083-2083
Author(s):  
Bing Xu ◽  
Yuanfei Shi ◽  
Long Liu ◽  
Bing Z Carter
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Synthetic Lethality ◽  
Leukemic Cells ◽  
Apoptotic Pathway ◽  
P53 Status ◽  
Acute Myeloid

BCL-2 inhibition exerts effective pro-apoptotic activities in acute myeloid leukemia (AML) but clinical efficacy as a monotherapy was limited in part due to the treatment-induced MCL-1 increase. Triptolide (TPL) exhibits anti-tumor activities in part by upregulating pro-apoptotic BCL-2 proteins and decreasing MCL-1 expression in various malignant cells. We hypothesized that combined BCL-2 inhibition and TPL exert synergistic anti-leukemia activities and prevent the resistance to BCL-2 inhibition in AML. We here report that TPL combined with BCL-2 inhibitor ABT-199 synergistically induced apoptosis in leukemic cells regardless of p53 status through activating the intrinsic mitochondrial apoptotic pathway in vitro. Although ABT-199 or TPL alone inhibited AML growth in vivo, the combination therapy demonstrated a significantly stronger anti-leukemic effect. Mechanistically, TPL significantly upregulated BH3 only proteins including PUMA, NOXA, BID and BIM and decreased MCL-1 but upregulated BCL-2 expression in both p53 wild type and p53 mutant AML cell lines, while the combination decreased both BCL-2 and MCL-1 and further increased BH3 only BCL-2 proteins. MCL-1 and BCL-2 increases associated with respective ABT-199 and TPL treatment and resistance were also observed in vivo. Significantly downregulating MCL-1 and elevating BH3 only proteins by TPL could not only potentially block MCL-1-mediated resistance but also enhance anti-leukemic efficacy of ABT-199. Conversely, BCL-2 inhibition counteracted the potential resistance of TPL mediated by upregulation of BCL-2. The combination further amplified the effect, which likely contributed to the synthetic lethality. This mutual blockade of potential resistance provides a rational basis for the promising clinical application of TPL and BCL-2 inhibition in AML independent of p53 status. Disclosures Carter: Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding.

Characterization of a hierarchy in human acute myeloid leukemia progenitor cells

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4754-4761 ◽  
Author(s):  
HJ Sutherland ◽  
A Blair ◽  
RW Zapf
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Proliferative Potential ◽  
Average Output ◽  
Human Acute Myeloid Leukemia ◽  
Leukemic Clone ◽  
Acute Myeloid

Despite the usual uniform and primitive appearance of cells derived from the leukemic clone in most patients with acute myeloid leukemia (AML), there is considerable heterogeneity among leukemic blasts, particularly with respect to their capacity to proliferate and/or self renew. We have assessed whether these differences in proliferative potential are correlated with the phenotypic changes that characterize normal hematopoiesis, which might suggest an analogous hierarchy of AML progenitors. We have used the ability of primitive AML cells to persist or produce blast colony forming cells (CFU-blast) detected after 2 to 8 weeks in the presence of growth factors in suspension cultures (SC) termed SC-initiating cells (IC), or with stroma in long-term cultures (LTC-IC) as a quantitative assay for a cell that may have primitive characteristics. This SC assay is linear, cell concentration independent, and the frequency of SC-IC by limiting dilution analysis is lower than primary CFU-blast. The average output of CFU-blast after 2 to 8 weeks by individual SC-IC varied between 2 and more than 100 in individual patients. Leukemic blasts were sorted based on their expression of antigens previously found useful to characterize normal progenitor differentiation, and analyzed for the percentage of CFU- blast SC-IC, and leukemic LTC-IC within each fraction. All of these progenitor types were heterogeneous in their expression of CD45RA and CD33, but expressed uniformly low levels of CD15 and differed from normal primitive progenitors in their high expression of HLA-DR. CFU- blast had a significantly higher expression of CD71 and CD38 as compared with SC-IC or leukemic LTC-IC. In patients with CD34+ blasts, the majority of their SC-IC at 4 weeks were CD34+/CD38-; however, patients with CD34- blasts had at least some CD34- progenitors. These results show that while heterogeneity exists between patients, it is possible to physically separate subpopulations of AML cells with different proliferative potentials. It also provides some support for the concept that quantitation of leukemic cells capable of producing CFU-blast for 4 weeks or more in vitro measures a less frequent leukemic progenitor with higher proliferative potential that may be the only relevant cell for maintaining the leukemic clone in vivo.

Acute Myeloid Leukemia Induced by MLL-ENL Is Cured by Oncogene Ablation despite Acquisition of Complex Genetic Abnormalities

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3109-3109
Author(s):  
Sarah J. Horton ◽  
Vanessa Walf-Vorderwülbecke ◽  
Steve J. Chatters ◽  
Neil J. Sebire ◽  
Jasper de Boer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Constitutive Expression ◽  
Leukemic Cells ◽  
Fusion Activity ◽  
Genetic Abnormalities ◽  
Conditional Expression ◽  
Acute Myeloid

Abstract Chromosomal translocations involving the Mixed-Lineage-Leukemia (MLL) gene on chromosome 11q23 are frequent in infant acute leukemia and give rise to the formation of MLL-fusion genes. Several studies have addressed the importance of MLL-fusion activity for the initiation and maintenance of hematopoietic transformation. However, the dependence of established leukemias on MLL-fusion activity has not been previously addressed. We have developed a model for conditional expression of MLL-ENL in hematopoietic progenitor cells, in which expression of the fusion oncogene is turned off by doxycycline. In this study, immortalized myeloid cells conditionally or constitutively expressing the MLL-ENL fusion gene were used to induce acute myeloid leukemia (AML) in vivo. Primary recipients developed AML with a mean latency of 81.4 (±4.8) days. Secondary recipients developed AML with much shorter latencies than primary recipients regardless of whether the leukemic cells were freshly transplanted (26.8 (±6.8) days) or cultured in vitro for one month prior to transplantation (18 (±3.9) days). Genetic analysis revealed that some leukemic cells had acquired gross chromosomal abnormalities such as trisomy 6 or gains and losses of chromosome regions, which were not detected in the immortalised cells from which they were derived. Despite the acquisition of additional genetic abnormalities, the leukemic cells remained dependent upon MLL-ENL expression in vitro and in vivo. The leukemic cells terminally differentiated into neutrophils upon doxycycline treatment in vitro and established leukemias regressed following administration of doxycycline to recipient mice in their drinking water. Leukemic regression was accompanied by the complete loss of leukemic cells from the peripheral blood and differentiation of leukemic cells in the spleen. In 7 out of 34 doxycycline treated mice, remission was not sustained and the leukemias relapsed. However, most of these were shown to have acquired constitutive expression of MLL-ENL. This study demonstrates that leukemic cells are addicted to MLL-ENL expression and suggests that targeting the transcriptional/signalling networks established by MLL-fusion oncogenes in patients with 11q23 rearrangements would be a major therapeutic advance.

The Dual E-Selectin/CXCR4 Inhibitor, GMI-1359, Enhances Efficacy of Anti-Leukemia Chemotherapy in FLT3-ITD Mutated Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3790-3790 ◽  
Author(s):  
Weiguo Zhang ◽  
Nalini Patel ◽  
William E. Fogler ◽  
John L. Magnani ◽  
Michael Andreeff
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cell ◽  
Cxcr4 Expression ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Acute Myeloid ◽  
Cells Cultured

Abstract Aberrant activation of the FMS-like tyrosine kinase-3 (FLT3) is driven by internal tandem duplication (ITD) mutations in the FLT3 gene, which are commonly observed in patients with acute myeloid leukemia (AML). Hence, FLT3 represents an attractive therapeutic target in AML (Weisberg et al., 2002). Indeed, several small molecule FLT3 inhibitors including sorafenib have showed encouraging efficacy in reducing leukemia blasts in the peripheral blood in FLT3 mutated AML patients. However, these agents have little effect on leukemic stem cells in the bone marrow (BM) microenvironment (Borthakur et al., 2011; Fathi and Chabner, 2011; Zhang et al., 2008). The BM microenvironment is enriched with cytokines and adhesion molecules, such as CXCR4 and E-selectin, which are believed to provide AML cells protection against chemotherapeutic agents (Horacek et al., 2013; Peled and Tavor, 2013). In fact, treatment with sorafenib markedly upregulated CXCR4 levels in FLT3 -mutated cells. In addition, leukemia cells can activate endothelial cells (EC) that induce adhesion of a sub-set of the leukemia cells through E-selectin. The adherent AML cells are sequestered in a nonproliferative state that further protects them from chemotherapy (Pezeshkian et al., 2013). Therefore, blocking CXCR4 and E-selectin in parallel could theoretically eliminate the protection provided by the interaction of leukemic cells with their BM microenvironment and enhance effectiveness of chemotherapy in FLT3-mutant AML patients. In the present study, we evaluated the effectiveness of a dual CXCR4 and E-selectin antagonist, GMI-1359 (GlycoMimetics, Inc., Rockville, MD), in targeting FLT3-ITD-mutant AML in vitro and in vivo. High levels of CXCR4 expression were observed in several human and murine AML cell lines, which was further increased in hypoxic (i.e., 1% oxygen) conditions that mimic the BM microenvironment. These FLT3 -ITD leukemic cell lines also expressed hypoxia-responsive, functional E-selectin ligands identified by reactivity with an antibody (HECA452) that binds the same carbohydrate epitope required for binding to E-selectin. One such E-selectin ligand CD44 increased in FLT3 -ITD cells cultured in hypoxia compared to those cultured in normoxia (i.e. 21% oxygen). In addition, hypoxia also enhanced CXCR4 expression on mesenchymal stem cells (MSC) and EC such as HUVEC. In hypoxic co-cultures of the FLT3 -ITD-mutant leukemia cells MV4-11 or MOLM14 with MSCs and ECs (i.e., HUVEC or TeloHAEC), the presence of the dual E-selectin/CXCR4 inhibitor GMI-1359 effectively reduced leukemic cell adhesion by ~ 50% to the MSC/EC feeder layer compared to the PBS-treated control (p<0.05), even in the presence of TNFa, which induces E-selectin expression in EC. However, an E-selectin specific inhibitor only reduced adhesion of MV4-11 and MOLM14 by ~ 20%. GMI-1359 markedly abrogated the protection provided by the BM microenvironment (i.e., hypoxia and/or MSC and EC) of Baf3-FLT3 -ITD leukemic cells treated with the FLT3 inhibitor sorafenib. Apoptosis was induced in 36.6%, 35.6% and 48.9% of leukemic cells cultured with sorafenib alone, sorafenib and an E-selectin inhibitor or sorafenib and GMI-1359, respectively. The significance of these in vitro findings were studied in vivo. Female SCID beige mice were injected iv with MV4-11 and followed for survival. Beginning 14 days post tumor injection, cohorts of mice (n=10/group) were treated with saline, GMI-1359 (40 mg/kg), standard chemotherapy cytarabine plus daunorubicin, or a combination of GMI-1359 and chemotherapy. Combined treatment of mice with GMI-1359 (40 mg/kg) and chemotherapy demonstrated a profound survival benefit compared to controls or chemotherapy alone at day 135 after leukemia cell injection (i.e., 67% vs. 11% or 30%, p=0.0011 and 0.0406, respectively). Single agent treatment with GMI-1359 was statistically indistinguishable from saline alone or chemotherapy alone. In a separate cohort of MV4.11-engrafted mice, the single administration of GMI-1359 increased circulating WBC and leukemic MV4-11cells, which persisted for at least 8 hrs. This effect was consistent with GMI-1359 disrupting the protective effects of the tumor microenvironment and mobilizing MV4-11 cells from the BM niche.. These findings provide the pre-clinical basis for the evaluation of GMI-1359 in patients with FLT3 -mutant AML. Figure 1. Figure 1. Disclosures Zhang: Karyopharm: Research Funding. Fogler:GlycoMimetics, Inc.: Employment. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

P-Glycoprotein Inhibitor Valspodar (PSC 833) Increases the Intracellular Concentrations of Daunorubicin In Vivo in Patients With P-Glycoprotein–Positive Acute Myeloid Leukemia

2000 ◽  
Vol 18 (9) ◽  
pp. 1837-1844 ◽  
Author(s):  
U. Tidefelt ◽  
J. Liliemark ◽  
A. Gruber ◽  
E. Liliemark ◽  
B. Sundman-Engberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Area Under The Curve ◽  
Leukemic Cells ◽  
Psc 833 ◽  
P Glycoprotein ◽  
Significant Difference ◽  
The Mean ◽  
Acute Myeloid

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment.PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)–positive. dnr 100 mg/m2was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography.RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 μmol/L in Pgp-negative samples and 13.5 μmol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 μmol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P < .05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed.CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 698-707 ◽  
Author(s):  
Wei Liu ◽  
Meng Guo ◽  
Ya-Bei Xu ◽  
Dao Li ◽  
Zhao-Nian Zhou ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Differentiation ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Intermittent Hypoxia ◽  
Leukemic Cells ◽  
In Vivo Effects ◽  
Acute Myeloid

AbstractWe showed previously that mild real hypoxia and hypoxia-mimetic agents induced in vitro cell differentiation of acute myeloid leukemia (AML). We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RARα transgenic mouse model of AML. For intermittent hypoxia, leukemic mice were housed in a hypoxia chamber equivalent to an altitude of 6000 m for 18 hours every consecutive day. The results show that intermittent hypoxia significantly prolongs the survival of the leukemic mice that received transplants, although it fails to cure the disease. By histologic and cytologic analyses, intermittent hypoxia is shown to inhibit the infiltration of leukemic blasts in peripheral blood, bone marrow, spleen, and liver without apoptosis induction. More intriguingly, intermittent hypoxia also induces leukemic cells to undergo differentiation with progressive increase of hypoxia-inducible factor-1α protein, as evidenced by morphologic criteria of maturating myeloid cells and increased expression of mouse myeloid cell differentiation–related antigens Gr-1 and Mac-1. Taken together, this study represents the first attempt to characterize the in vivo effects of hypoxia on an AML mouse model. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML.

scholarly journals The Role of T Cell Immunotherapy in Acute Myeloid Leukemia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3376
Author(s):  
Fang Hao ◽  
Christine Sholy ◽  
Chen Wang ◽  
Min Cao ◽  
Xunlei Kang
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Leukemic Cells ◽  
Cytotoxic T Cell ◽  
Cell Phenotype ◽  
T Cell Therapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed.

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