scholarly journals Chidamide increases the sensitivity of refractory or relapsed acute myeloid leukemia cells to anthracyclines via regulation of the HDAC3 -AKT-P21-CDK2 signaling pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Hao Wang ◽  
Yu-chen Liu ◽  
Cheng-ying Zhu ◽  
Fei Yan ◽  
Meng-zhen Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathway ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Complete Response ◽  
Dependent Manner ◽  
Induce Cell Cycle Arrest ◽  
Anthracycline Resistance ◽  
Acute Myeloid ◽  
Resistant Cells

Abstract Background Induction therapy for acute myeloid leukemia (AML) is an anthracycline-based chemotherapy regimen. However, many patients experience a relapse or exhibit refractory disease (R/R). There is an urgent need for more effective regimens to reverse anthracycline resistance in these patients. Methods In this paper, Twenty-seven R/R AML patients with anthracycline resistance consecutively received chidamide in combination with anthracycline-based regimen as salvage therapy at the Chinese PLA General Hospital. Results Of the 27 patients who had received one course of salvage therapy, 13 achieved a complete response and 1 achieved a partial response. We found that the HDAC3-AKT-P21-CDK2 signaling pathway was significantly upregulated in anthracycline-resistant AML cells compared to non-resistant cells. AML patients with higher levels of HDAC3 had lower event-free survival (EFS) and overall survival (OS) rates. Moreover, anthracycline-resistant AML cells are susceptible to chidamide, a histone deacetylase inhibitor which can inhibit cell proliferation, increase cell apoptosis and induce cell-cycle arrest in a time- and dose-dependent manner. Chidamide increases the sensitivity of anthracycline-resistant cells to anthracycline drugs, and these effects are associated with the inhibition of the HDAC3-AKT-P21-CDK2 signaling pathway. Conclusion Chidamide can increase anthracycline drug sensitivity by inhibiting HDAC3-AKT-P21-CDK2 signaling pathway, thus demonstrating the potential for application.

Survival Outcomes in Relapsed/Refractory Acute Myeloid Leukemia Patients Who Achieve Less-than-Complete Response After First Salvage Therapy

2014 ◽  
Vol 14 ◽  
pp. S127
Author(s):  
Shilpan Shah ◽  
Hagop Kantarjian ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Complete Response ◽  
Survival Outcomes ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Decitabine as salvage therapy for primary induction failure of acute myeloid leukemia

2017 ◽  
Vol 56 (8) ◽  
pp. 1120-1121 ◽  
Author(s):  
Pasquale Niscola ◽  
Benedetta Neri ◽  
Gianfranco Catalano ◽  
Luciana Morino ◽  
Marco Giovannini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid

Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia

2018 ◽  
Vol 141 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Li Wang ◽  
Jun Xu ◽  
Xiaolong Tian ◽  
Tingting Lv ◽  
Guolin Yuan
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Remission Rate ◽  
Chinese Patients ◽  
Acute Myeloid

Background/Aims: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. Methods: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1–5), 2 g/m2/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5). The median follow-up duration was 10 months. Results: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 ± 6.0% and 3-year OS of 16.7 ± 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts ≥42.1% were correlated with an unfavorable CR. Secondary disease, age ≥60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). Conclusion: CLAG was effective and well tolerated for R/R AML. BM blasts ≥42.1%, age ≥60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis.

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.

scholarly journals All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Chi Huu Nguyen ◽  
Katharina Bauer ◽  
Hubert Hackl ◽  
Angela Schlerka ◽  
Elisabeth Koller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

AbstractEcotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

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