scholarly journals AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Sean M. Post ◽  
Huaxian Ma ◽  
Prerna Malaney ◽  
Xiaorui Zhang ◽  
Marisa J.L. Aitken ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell ◽  
Resistant Cells

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in AML. The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor ONO-7475 kills FLT3-mutant acute myeloid leukemia cells with targets including Extracellular-signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single agent in vivo using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO- 7475/ABT-199 was even more potent in reducing leukemic burden and prolonging survival of mice in both model systems. These results suggest the ONO-7475/ABT-199 combination may be effective for acute myeloid leukemia therapy.

scholarly journals Monocyte-macrophage differentiation of acute myeloid leukemia cell lines by small molecules identified through interrogation of the Connectivity Map database

Cell Cycle ◽  
2015 ◽  
Vol 14 (16) ◽  
pp. 2578-2589 ◽  
Author(s):  
Gloria Manzotti ◽  
Sandra Parenti ◽  
Giovanna Ferrari-Amorotti ◽  
Angela Rachele Soliera ◽  
Sara Cattelani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Small Molecules ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Connectivity Map ◽  
Macrophage Differentiation ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Acute myeloid leukemia cell lines MOLM-17 and MOLM-18 derived from patient with advanced myelodysplastic syndromes

2005 ◽  
Vol 29 (6) ◽  
pp. 701-710 ◽  
Author(s):  
Yoshinobu Matsuo ◽  
Hans G. Drexler ◽  
Akira Harashima ◽  
Ayumi Okochi ◽  
Kensuke Kojima ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Acute Myeloid Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

In Vitro and In Vivo Monitoring of Valproic Acid Effects on Gene Expression Signatures in Adult Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2605-2605
Author(s):  
Lars Bullinger ◽  
Konstanze Dohner ◽  
Richard F. Schlenk ◽  
Frank G. Rucker ◽  
Jonathan R. Pollack ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Serum Levels ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. To define an VPA in vitro “response signature” we profiled gene expression in myeloid leukemia cell lines (HL-60, NB-4, HEL-1, CMK and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. In accordance with previous studies in vitro VPA treatment of myeloid cell lines induced the expression of the cyclin-dependent kinase inhibitors CDKN1A and CDKN2D coding for p21 and p19, respectively. Supervised analyses revealed many genes known to be associated with a G1 arrest. In all cell lines except for CMK we examined an up-regulation of TNFSF10 coding for TRAIL, as well as differential regulation of other genes involved in apoptosis. Furthermore, gene set enrichment analyses showed a significant down-regulation of genes involved in DNA metabolism and DNA repair. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age<60yrs) and within the AMLSG 06-04 trial for older adults (age>60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA. First results from our ongoing analysis of in vivo VPA treated samples are in accordance with our cell line experiments as e.g. we also see an induction of CDKN1A expression. However, the picture observed is less homogenous as concomitant administration of ICE, as well as other factors, like e.g. VPA serum levels, might substantially influence the in vivo VPA response. Nevertheless, our data are likely to provide new insights into the VPA effect in vivo, and this study may proof to be useful to predict AML patients likely to benefit from VPA treatment. To achieve this goal, we are currently analyzing additional samples, and we are planning to correlate gene expression findings with histone acetylation status, VPA serum levels, cytogenetic, and molecular genetic data.

Nampt/SIRT2 Hyperactivation Lead to Activation of ß-Catenin: a Possible Mechanism of Leukomogenic Transformation In CN Patients.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1486-1486
Author(s):  
Lan Dan ◽  
Ana Gigina ◽  
Karl Welte ◽  
Julia Skokowa
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cells ◽  
Nuclear Accumulation ◽  
Healthy Individuals ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Abstract 1486 Recently we demonstrated that nicotinamide phosphoribosyltransferase (NAMPT) is an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis via activation of NAD+/sirtuins/C/EBPs signaling cascade. Nampt levels were significantly elevated in plasma and in myeloid cells of patients with severe congenital neutropenia (CN). CN is characterized by a “maturation arrest” of granulopoiesis on the promyelocytic stage of differentiation and by leukemogenic tansformation of hematopoiesis in ca. 20 % of patients. The mechanism of the leukemic transformation is still unclear. Previously, we reported elevated levels of activated oncogene ß-catenin in nuclei of myeloid progenitor cells of CN patients. The activity and nuclear translocation of ß-catenin is regulated by glycogen synthase kinase-3 ß (GSK3ß), which activates ß-catenin degradation complex. In the present study we found that in myeloid cells of CN patients GSK3ß was inhibited by phosphorylation on Ser9, as compared to healthy individuals. Therefore, we assume that GSK3ß-ß-catenin pathway could be involved in the leukemogenic transformation of hematopoiesis. Since, Nampt was also elevated in CN patients, we aimed to investigate the connection between hyperactivated Nampt and ß-catenin in leukemogenesis. The Nampt functions in hematopoiesis are dependent on the dose of Nampt and NAD+. Thus, in vitro stimulation of CD34+ cells with Nampt led to granulocytic differentiation via activation of sirtuin/C/EBP-dependent pathway. At the same time, inhibitors of NAMPT have been identified as therapeutical targets for some cancers including leukemia. This suggested that different mechanisms are operating downstream of NAMPT in the “normal” and leukemogenic myeloid cells. Screening of the different sirtuins in primary acute myeloid leukemia (AML) blasts revealed significant upregulation of SIRT2 mRNA and protein levels, as compared to CD34+ and CD33+ hematopoietic cells of healthy individuals. SIRT2 levels were also elevated in myeloid cells of CN patients treated with G-CSF. Specific inhibition of NAMPT (using 10 nMol of FK866) or SIRT2 (using 100nMol of AC93253) significantly reduced proliferation and induced apoptosis in human myeloid leukemia cell lines (NB4, HL60 and U937). We further tested if inhibition of Nampt or SIRT2 has an effect on GSK3ß/ß-catenin pathway. GSK3ß is known to be inhibited by Akt and treatment of the acute myeloid leukemia cell lines NB4 and HL60 with FK866 or AC93253 resulted in the activation of Akt via phosphorylation on Thr308 and Ser473 and inactivation of GSK-3ß via inhibition of phosphorylation on Ser9. Moreover, activated ß-catenin protein was almost completely disappeared from the nucleus of cells treated with FK866. Taken together, our results provide strong evidence that NAMPT and SIRT2 participate in leukemogenic transformation via inactivation of GSK3ß leading to nuclear accumulation of oncogenic ß-catenin. Disclosures: No relevant conflicts of interest to declare.

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