Enasidenib-induced differentiation promotes sensitivity to venetoclax in IDH2-mutated acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Severine Cathelin ◽  
David Sharon ◽  
Amit Subedi ◽  
Dan Cojocari ◽  
Darren C. Phillips ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Induced Differentiation ◽  
Acute Myeloid

A Novel Path for ATRA Differentiation Therapy in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3727-3727
Author(s):  
Jean-Emmanuel Sarry ◽  
Helena Boutzen ◽  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Granulocytic Differentiation ◽  
Induced Differentiation ◽  
Idh1 R132h ◽  
Recurrent Mutations ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is characterized by accumulation of malignant blasts with impaired differentiation programs due to recurrent mutations, among which IDH mutations occur in 15% of AML patients. These mutations lead to a block in erythroid commitment while they may also bias hematopoietic differentiation to myeloid lineage. Interestingly, Lyn tyrosine kinase is required for erythroid differentiation and we have observed a reduction of Lyn expression in the presence of IDH1-R132H mutation. It is also a negative regulator of ATRA-induced granulocytic differentiation. Accordingly, we hypothesized that IDH mutations may sensitize AML cells to ATRA-induced differentiation. Here, we report that clinically achievable doses of ATRA are sufficient to trigger differentiation specifically on AML cell lines, primary patient samples and xenograft mice models carrying IDH1 mutation as observed by an increase in CD11b expression, granulocytic enzyme activity and morphologic changes in May-Grunwald-Giemsa staining. We also showed that ATRA-induced terminal granulocytic differentiation increases apoptosis while decreases proliferation and colony formation specifically in IDH1 mutant cells. Moreover, inhibition of IDH1-R132H activity reduced ATRA-sensitivity while increasing expression of IDH mutation correlated with highest ATRA sensitivity. Furthermore, treatment with a cell-permeable form of the oncometabolite specifically produced by the mutant (eg. 2-HydroxyGlutarate) sensitized AML cells to ATRA-induced differentiation. Finally, because ATRA-induced differentiation triggers a transient increase of Lyn activation, its association with Lyn inhibitors synergistically increased ATRA-induced differentiation of IDH mutant blasts. In summary, our results showed that IDH mutations by producing 2-HG sensitized leukemic blasts to ATRA and that this synergizes with Lyn inhibition. Since 2HG concentration reaches millimolar in AML patient serum and is 100-fold higher in IDH mutated patients than in non-mutated ones, we would predict a strong efficacy and specificity of ATRA. Furthermore, as IDH mutations are systematically conserved at relapse, this therapeutic strategy might be promising to achieve a long-term remission specifically for this AML patient subgroup. Disclosures No relevant conflicts of interest to declare.

scholarly journals Enzasataurin Enhances ATRA-induced Differentiation of Acute Myeloid Leukemia Cells

2020 ◽  
Author(s):  
Ze-yi Li ◽  
Cui Liang ◽  
Ming Ding ◽  
Xiang-qin Weng ◽  
yan Sheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Specific Inhibitor ◽  
Akt Inhibitor ◽  
Induced Differentiation ◽  
Cd11b Expression ◽  
Akt Activation ◽  
Protein Levels ◽  
Acute Myeloid

Abstract Background All-trans retinoic acid (ATRA) is considered to be the sole clinically useful differentiating agent in the treatment of acute myeloid leukemia (AML). However, it has been effective only in acute promyelocytic leukemia (APL) but not other subtypes of AML. Therefore, finding strategies to sensitize cells to ATRA may develop ATRA-based therapy in the treatment of non-APL AML patients. Methods Cell proliferation was assessed by cell growth. Cell death was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11b expression and morphology. To explore the underlying mechanisms, we studied the role of PKCβ, MEK, ERK, AKT, PU.1, C/EBPβ and C/EBPε by Western-blotting analysis. Results In this study, a clinically achievable concentration of enzastaurin enhanced ATRA-induced differentiation of AML cell lines, HL-60 and U937 as well as non-APL AML primary cells, while it also restored ATRA sensitivity in ATRA-resistant cell line, HL-60Res. Mechanistically, in all these cell lines, enzastaurin-ATRA (enz-ATRA) enhanced the protein levels of PU.1, CCAAT/enhancer binding protein β (C/EBPβ) and C/EBPε. The activity of protein kinase C β (PKCβ) was suppressed by enz-ATRA treatment in HL-60 and HL-60Res cells. However, another PKCβ-selective inhibitor mimicked the cellular and molecular effects of enzastaurin only in HL-60 cells. Only in U937 cells, enz-ATRA activated MEK and ERK, and a MEK specific inhibitor suppressed enz-ATRA-triggered differentiation and reduced the protein levels of PU.1, C/EBPβ and C/EBPε. Enz-ATRA activated Akt in HL-60 and HL-60Res cells. However, an Akt inhibitor blocked enz-ATRA-triggered differentiation and restored the protein levels of PU.1, C/EBPβ and C/EBPε only in HL-60Res cells. Therefore, PKCβ inhibition, MEK/ERK and Akt activation are involved in enz-ATRA-induced differentiation in HL-60, U937 and HL-60Res cells, respectively by modulation of the protein levels of C/EBPβ, C/EBPε and PU.1. Conclusions Enzastaurin, at the clinically achievable concentration, enhances ATRA-induced differentiation of AML cells by PKCβ inhibition, MEK/ERK and Akt activation. This study may provide a potential therapeutic strategy for AML patients.

scholarly journals 5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Vilma Dembitz ◽  
Hrvoje Lalic ◽  
Ivan Kodvanj ◽  
Barbara Tomic ◽  
Josip Batinic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Cell Lineage ◽  
Induced Differentiation ◽  
Monocytic Cell ◽  
Partial Data ◽  
Hematopoietic Cell Lineage ◽  
Acute Myeloid

Abstract Background All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA. Methods Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0. Results AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage. Conclusion AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.

Decitabine-Induced Differentiation Syndrome in a Patient with Acute Myeloid Leukemia: A Case Report.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4528-4528
Author(s):  
William Blum ◽  
Kristie A. Blum ◽  
Cheryl Kefauver ◽  
Mollie Moran ◽  
Kenneth Chan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Low Dose ◽  
Myeloid Differentiation ◽  
Induced Differentiation ◽  
Retinoic Acid Syndrome ◽  
Acute Myeloid

Abstract We report here for the first time a case of “decitabine-induced differentiation syndrome” in a patient (pt) with acute myeloid leukemia (AML). The cytosine analog decitabine, after incorporating into DNA, irreversibly binds DNA methyltransferase (DNMT) enzymes where cytosine residues are targeted for methylation. This allows replication of unmethylated DNA with subsequent re-expression of genes previously silenced by promoter methylation. It has been suggested that decitabine at low doses may have differentiating effects, as compared to cytotoxic effects at higher doses. A previous phase I trial demonstrated clinical activity of low dose decitabine in patients with myeloid malignancies (Issa, et al., Blood 2004). Given the close relationship of DNA methylation and histone deacetylation in modulating gene expression, we are currently conducting a phase I trial (OSU 0336) of low dose decitabine (15mg/m2 IV over 1 hour on days 1–10) alone (step 1) or in combination with escalating doses of the histone deacetylase inhibitor valproic acid (step 2) in AML. An 82 year old male pt with untreated, secondary AML (65% bone marrow blasts, 95% marrow cellularity) was enrolled on step 1 of the study and given 15mg/m2/day of decitabine for 10 consecutive days. At the time of initiation of therapy, the pt had a white blood cell (WBC) count of 8,700/uL with absolute neutrophil count (ANC) of 1,500/uL and absolute blast count (ABC) of 3,200/uL. At day 11, the pt had WBC 1,000/uL with ANC of 450/uL and ABC of 150/uL and was clinically well. However, at day 17, he presented with cough and shortness of breath, without fever. WBC had risen to 18,700/uL with ANC of 11,000/uL and ABC of 750/uL. The patient developed worsening hypoxia and required mechanical ventilation. Chest radiograph demonstrated diffuse interstitial infiltrates, but bronchoscopy and lavage (on day 18 and repeated on day 24) did not identify an infectious etiology. Due to clinical concern for a differentiation syndrome similar to the “retinoic acid syndrome” occurring in acute promyelocytic leukemia patients treated with all-trans-retinoic-acid (ATRA), the pt was started on dexamethasone 10mg IV q12 hours beginning on day 18, in addition to broad spectrum antimicrobial coverage. Peripheral blood smears during the following week showed evidence of myeloid differentiation, and by day 25 no circulating blasts were found (WBC 4,300/uL, ANC 3,000/uL) while the overall clinical condition improved. The pt was finally extubated on day 38 but within 24 hours required emergent re-intubation due to nasogastric feeding aspiration and died at day 53. In summary, these preliminary data support the biological activity of low dose decitabine in AML and suggest that clinical precautions similar to those implemented for the “retinoic acid syndrome” in ATRA-treated APL should be considered in decitabine-treated AML when myeloid differentiation and rising neutrophil counts are observed.

scholarly journals Cell-Type-Specific Effects of Silibinin on Vitamin D-Induced Differentiation of Acute Myeloid Leukemia Cells Are Associated with Differential Modulation of RXRα Levels

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Rina Wassermann ◽  
Victoria Novik ◽  
Michael Danilenko
Keyword(s):  
Vitamin D ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
U937 Cells ◽  
Differential Modulation ◽  
Cell Type ◽  
Induced Differentiation ◽  
Response Element ◽  
Cell Type Specific ◽  
Acute Myeloid

Plant polyphenols have been shown to enhance the differentiation of acute myeloid leukemia (AML) cells induced by the hormonal form of vitamin D3 (1α,25-dihydroxyvitamin D3; 1,25D). However, how these agents modulate 1,25D effects in different subtypes of AML cells remains poorly understood. Here, we show that both carnosic acid (CA) and silibinin (SIL) synergistically enhancd 1,25D-induced differentiation of myeloblastic HL60 cells. However, in promonocytic U937 cells, only CA caused potentiation while SIL attenuated 1,25D effect. The enhanced effect of 1,25D+CA was accompanied by increases in both the vitamin D receptor (VDR) and retinoid X receptor alpha (RXRα) protein levels and vitamin D response element (VDRE) transactivation in both cell lines. Similar increases were observed in HL60 cells treated with 1,25D + SIL. In U937 cells, however, SIL inhibited 1,25D-induced VDRE transactivation concomitant with downregulation of RXRα at both transcriptional and posttranscriptional levels. These inhibitory effects correlated with the inability of SIL, with or without 1,25D, to activate the Nrf2/antioxidant response element signaling pathway in U937 cells. These results suggest that opposite effects of SIL on 1,25D-induced differentiation of HL60 and U937 cells may be determined by cell-type-specific signaling and transcriptional responses to this polyphenol resulting in differential modulation of RXRα expression.

scholarly journals Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway

Leukemia ◽  
2016 ◽  
Vol 31 (5) ◽  
pp. 1154-1165 ◽  
Author(s):  
J Xin ◽  
D You ◽  
P Breslin ◽  
J Li ◽  
J Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Induced Differentiation ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid
Sign in / Sign up

Export Citation Format

Share Document