scholarly journals Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Godelieve Meunier ◽  
Rudy Birsen ◽  
Clarisse Cazelles ◽  
Maya Belhadj ◽  
Lilia Cantero-Aguilar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Specific Inhibitor ◽  
Vesicular Trafficking ◽  
Class Iii ◽  
Antileukemic Activity ◽  
Lipid Kinase ◽  
Mtorc1 Signaling ◽  
Vacuolar Protein ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and l-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.

scholarly journals Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Adriana E. Tron ◽  
Matthew A. Belmonte ◽  
Ammar Adam ◽  
Brian M. Aquila ◽  
Lawrence H. Boise ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Specific Inhibitor ◽  
Acute Myeloid

Alternative polyadenylation dysregulation contributes to the differentiation block of acute myeloid leukemia

Blood ◽  
2021 ◽  
Author(s):  
Amanda G Davis ◽  
Daniel T. Johnson ◽  
Dinghai Zheng ◽  
Ruijia Wang ◽  
Nathan D. Jayne ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Alternative Polyadenylation ◽  
Hematopoietic Stem ◽  
Global Trends ◽  
Protein Levels ◽  
Mtorc1 Signaling ◽  
Differentiation Block ◽  
Acute Myeloid

Post-transcriptional regulation has emerged as a driver for leukemia development and an avenue for therapeutic targeting. Among post-transcriptional processes, alternative polyadenylation (APA) is globally dysregulated across cancer types. However, limited studies have focused on the prevalence and role of APA in myeloid leukemia. Furthermore, it is poorly understood how altered poly(A) site (PAS) usage of individual genes contributes to malignancy or whether targeting global APA patterns might alter oncogenic potential. In this study, we examined global APA dysregulation in acute myeloid leukemia (AML) patients by performing 3' Region Extraction And Deep Sequencing (3'READS) on a subset of AML patient samples along with healthy hematopoietic stem and progenitor cells (HSPCs) and by analyzing publicly available data from a broad AML patient cohort. We show that patient cells exhibit global 3' untranslated region (UTR) shortening and coding sequence (CDS) lengthening due to differences in PAS usage. Among APA regulators, expression of FIP1L1, one of the core cleavage and polyadenylation factors, correlated with the degree of APA dysregulation in our 3'READS dataset. Targeting global APA by FIP1L1 knockdown reversed the global trends seen in patients. Importantly, FIP1L1 knockdown induced differentiation of t(8;21) cells by promoting 3'UTR lengthening and downregulation of the fusion oncoprotein AML1-ETO. In non-t(8;21) cells, FIP1L1 knockdown also promoted differentiation by attenuating mTORC1 signaling and reducing MYC protein levels. Our study provides mechanistic insights into the role of APA in AML pathogenesis and indicates that targeting global APA patterns can overcome the differentiation block of AML patients.

scholarly journals High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 744-749 ◽  
Author(s):  
W Hiddemann ◽  
H Kreutzmann ◽  
K Straif ◽  
WD Ludwig ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Antileukemic Activity ◽  
First Line ◽  
Clinical Phase ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

scholarly journals Antigen-specific immunotherapies for acute myeloid leukemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 584-595 ◽  
Author(s):  
Sarah A. Buckley ◽  
Roland B. Walter
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Treatment Modalities ◽  
Target Antigen ◽  
Antileukemic Activity ◽  
Care Needs ◽  
Antibody Drug Conjugate ◽  
Acute Myeloid

Abstract Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody–drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard “3 + 7”-based chemotherapy have remained unsatisfactory in many patients.

Immunogenicity and Antileukemic Activity of Dendritic Cells Electroporated with Wilms’ Tumor WT1 mRNA: A Phase I/II Trial in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 830-830 ◽  
Author(s):  
Zwi N. Berneman ◽  
Ann Van de Velde ◽  
Ann Van Driessche ◽  
Nathalie Cools ◽  
Barbara Stein ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Rna Expression ◽  
Antileukemic Activity ◽  
Dc Vaccines ◽  
Acute Myeloid

Abstract The Wilms’ tumor protein WT1 is a target for immunotherapy in malignancies, such as acute myeloid leukemia (AML). Following our demonstration that dendritic cells (DC) can be efficiently transfected by messenger (m)RNA electroporation (Van Tendeloo VF et al. Blood2001;98:49–56) and that WT1 mRNA-electroporated DC stimulate WT1-specific T cells in vitro (Van Driessche A et al. Leukemia2005;19:1863–1871), we performed a phase I/II dose-escalation trial, in which patients with AML in remission but at high risk of relapse and without a direct sib allo-transplant option (9 patients) or with slowly progressive AML (1 patient) received intradermal injections of WT1 RNA-loaded DC. Following apheresis and CD14 immunomagnetic monocyte separation, DC were generated in 6-day cultures in clinical-grade medium supplemented with serum, granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, matured with prostaglandin (PG)E2 and tumor necrosis factor (TNF)-alpha, harvested, electroporated with WT1 mRNA and used as vaccines. The patients received four biweekly DC vaccines and a delayed-type hypersensitivity (DTH) test was performed 2 weeks following the last vaccination. Patients were monitored for minimal residual disease (MRD) by analyzing WT1 RNA expression in peripheral blood by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (Cilloni D et al. Leukemia2002;16:2115–2121 & Cilloni D et al. Haematologica2008;93:921–924). Before and after vaccination, peripheral blood was collected for immunomonitoring purposes. Feasibility, safety, immunogenicity and effect on MRD were investigated. There was successful DC generation and vaccine production in all 10 patients. No serious adverse events or toxicity were observed and vaccinations were well tolerated. A decrease in WT1 RNA expression was observed during the course of the vaccination in 4/7 patients who had an increased WT1 mRNA level in peripheral blood. Three of those patients are still in complete hematological remission. An in vivo vaccine-specific immune response was demonstrated in 10/10 patients by DTH. Ex vivo immunomonitoring analysis showed a significant increase in circulating activated HLA-DR+ CD4+ T cells and in IL-2 plasma levels following vaccination. Importantly, in vitro restimulation assays of peripheral blood mononuclear cells revealed a significant postvaccination increase in interferon (IFN)-gamma-producing WT1-specific CD8+ T cells (n= 8 evaluable patients), but not in cytokine-producing WT1-specific CD4+ T cells. There was no significant change in WT1-specific antibodies following vaccination. We conclude that vaccination of AML patients with WT1 RNA-loaded DC is feasible and safe. Furthermore, the DC elicit vaccine-specific and WT1-specific CD8+ T-cell responses. The correlation between reduction of circulating WT1 mRNA and the administration of the DC vaccines strongly suggests that this DC vaccine elicits an antileukemic activity.

Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
U. Keilholz ◽  
A. Letsch ◽  
A. Asemissen ◽  
W. Hofmann ◽  
L. Uharek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Intracellular Cytokine Staining ◽  
T Cell Response ◽  
Antileukemic Activity ◽  
Acute Myeloid

2511 Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas. No significant financial relationships to disclose.

scholarly journals Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia

2017 ◽  
Vol 8 ◽  
Author(s):  
Yunbao Pan ◽  
Dong Liu ◽  
Yongchang Wei ◽  
Dan Su ◽  
Chenyang Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Azelaic Acid ◽  
Myeloid Leukemia ◽  
Antileukemic Activity ◽  
Acute Myeloid
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