scholarly journals DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eric Haines ◽  
Yuki Nishida ◽  
Michael I. Carr ◽  
Rafael Heinz Montoya ◽  
Lauren B. Ostermann ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Topoisomerase Ii ◽  
Therapeutic Potential ◽  
P53 Protein ◽  
Fixed Ratio ◽  
Myeloid Cell ◽  
Leukemia Cells ◽  
Topoisomerase Ii Inhibitors

AbstractPeposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.

Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice

Blood ◽  
2010 ◽  
Vol 116 (12) ◽  
pp. 2103-2111 ◽  
Author(s):  
Helena Ågerstam ◽  
Marcus Järås ◽  
Anna Andersson ◽  
Petra Johnels ◽  
Nils Hansen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Tyrosine Kinases ◽  
Cellular Proliferation ◽  
Myeloid Cell ◽  
Myeloproliferative Disorder ◽  
Immunodeficient Mice ◽  
Myeloproliferative Syndrome

Abstract The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34+ cells from umbilical-cord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1 or BCR/FGFR1 in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1 fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder.

scholarly journals Incorporating Hemoglobin Levels to Map Leukostasis Risk in Acute Leukemia Using Microvasculature-on-Chip Technologies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Jamie Oakley ◽  
Evelyn K. Williams ◽  
Christina Caruso ◽  
Yumiko Sakurai ◽  
Reginald Tran ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Blood Viscosity ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Cell Counts ◽  
On Chip ◽  
Wbc Count

Hyperleukocytosis, most commonly defined as a white blood cell (WBC) count > 100,000/μL, is an oncologic emergency in acute leukemia that can lead to leukostasis, which occurs when leukemia cells obstruct the microvasculature resulting in significant morbidity and mortality from neurologic (CNS hemorrhage, thrombosis) or pulmonary (respiratory distress, hypoxia) symptoms. The underlying mechanisms are poorly understood but are thought to be related to increased blood viscosity, secondary to high WBC count, leukemia cell aggregation, and the abnormal mechanical properties, size, and cell-cell interactions of leukemia cells. Leukapheresis is a commonly used therapy for rapid cytoreduction in symptomatic patients, but the procedure is not without risks. No existing methods reliably predict leukostasis or guide treatment including the commonly used WBC count, which only loosely correlates with leukostasis and does not accurately describe the blood viscosity at the microvascular level. Importantly, while hematocrit/hemoglobin levels (Hgb) are known to be major contributors to blood viscosity, they have not been systematically assessed in leukostasis risk, and Hgb often decreases as leukemic cell counts rise, complicating the issue. Incorporating Hgb levels may better predict leukostasis and assist physicians balancing the risk of hyperleukocytosis compared to the interventions themselves. To that end, we investigated how the differing presentations of acute leukemia lead to microvessel occlusion, thereby affecting effective blood viscosity at the microvascular level using "microvasculature-on-a-chip" devices that mimic the microvascular geometry (Figure 1) developed by our laboratory. This physiologically relevant microvascular model allows for in vitro investigation as in vivo studies are nearly impossible due to difficulty in visualizing and manipulating the animal microvasculature and cell counts. The devices were microfabricated using polydimethylsiloxane (PDMS). Acute T-cell lymphoblastic (Jurkat) and acute monocytic (THP-1) cell lines were maintained via standard cell culture conditions. Red cells from healthy donors were isolated and mixed with leukemia cells to achieve target Hgb and WBC levels. Various physiologic leukemia "mixtures" were then perfused under physiologic microcirculatory flow conditions through the microvascular device and microchannels occlusion was tracked via videomicroscopy (Figure 2). With T-cell leukemia, Hgb levels affected the risk of "in vitro leukostasis." Specifically, with severe anemia and WBC count less than the hyperleukocytosis range, time to microchannel occlusion was longer, and was more dependent on Hgb rather than WBC count. However, in cases with severe anemia and WBC counts > 100k/μL, WBC count exhibited a stronger effect on occlusion with little dependence on Hgb (Figure 3). At Hgb > 8g/dL, microchannel occlusion was dependent on WBC count regardless of hyperleukocytosis or not. In contrast, our data to date shows that with myeloid leukemia, in vitro leukostasis is not associated with Hgb levels, and is consistent with how myeloid leukemias in vivo cause leukostasis symptoms at lower WBC counts than lymphoid leukemias, not only due to size but also adhesive interactions. These data suggest when determining risk for leukostasis, WBC count should not be the sole determinant. Here we show Hgb levels affect microvascular blood viscosity and propensity for microvascular occlusion, but it appears to have a greater impact with T-cell leukemias versus myeloid leukemias (Figure 4). These studies indicate Hgb is an important clinical parameter for leukostasis risk in acute leukemia and will help inform guidelines for leukapheresis and even phlebotomy, a much simpler and safer procedure, to mitigate hyperviscosity in acute leukemia. These results can also impact decisions regarding the need for red blood cell transfusions, which iatrogenically increase blood viscosity. Studies incorporating patient myeloid and lymphoid leukemia cells and microvasculature-on-chip devices integrating live endothelium to assess leukemia cell adhesion are ongoing. Figure Disclosures Lam: Sanguina, Inc: Current equity holder in private company.

Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo

1995 ◽  
Vol 36 (2) ◽  
pp. 165-171 ◽  
Author(s):  
Sylvia A. Holden ◽  
B. A. Teicher ◽  
Michael F. Robinson ◽  
David Northey ◽  
Andre Rosowsky
Keyword(s):  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitors

scholarly journals A CRISPR/Cas9 Library Screen in Patients' Leukemia Cells In Vivo

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3945-3945
Author(s):  
Ehsan Bahrami ◽  
Martin Becker ◽  
Anna-Katharina Wirth ◽  
Jan Phillip Schmid ◽  
Tobias Herold ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Drop Out ◽  
Leukemia Cells ◽  
Functional Genomic ◽  
Cell Homing ◽  
Nsg Mice ◽  
Crispr Screen

Background: Functional genomic screens elegantly increase our understanding of biology of leukemias. So far, CRISPR/Cas9 screens are widely performed in cell lines and in genetically engineered mouse models, in vitro and in vivo; here, we extended their use to patient-derived leukemia cells in vivo. Methods Serially transplantable patient-derived xenograft (PDX) models were generated from children and adults with acute lymphoblastic leukemia (ALL). Cas9 was stably expressed in PDX ALL cells using a split form of Cas9 assembled by inteins, facilitating lentiviral-mediated gene delivery. Customized sgRNA library was generated using golden gate cloning, at 5 sgRNAs per target gene. The sgRNA vector additionally expressed a fluorochrome marker and a tag, for sequential magnetic-activated cell sorting (MACS) and flow cytometry (FACS) enrichment of sgRNA transduced PDX cells. Highly enriched Cas9/sgRNA double transgenic cells were transplanted into NSG mice and animals sacrificed after different periods of time. Cells were re-isolated from bone marrow, purified and subjected to PCR-based amplification of sgRNA library followed by next generation sequencing. Differential sgRNA distributions were analysed using a MAGeCK pipeline. Results We aimed to establish a comprehensive CRISPR screen pipeline allowing functional genomic screens in patients' acute leukemia cells. We investigated surface molecules required for cell homing and growth in mice, using a distinct customized sgRNA library. Quality controls of the sgRNA plasmid pool as well as transgenic PDX input samples verified standard distribution of all sgRNAs. As knockout was required at the time point of transplantation, conditions for prolonged culture of PDX ALL cells in vitro were optimized. Before injection into NSG mice, transduced PDX ALL cells were successfully enriched to above 95% using MACS and FACS. Over time in vivo, deep sequencing of re-isolated PDX cells revealed unchanged distribution of control sgRNAs, but strong loss of sgRNAs targeting CXCR4 and ITGB1, suggesting that CXCR4 and ITGB1 might be required for PDX ALL cell homing and engraftment. To validate the findings of drop-out CRISPR screen, we analyzed single sgRNAs targeting CXCR4 and ITGB1 in PDX cells. Competitive in vivo assays monitored by recombinant fluorochrome markers showed that the cells with CXCR4 or ITGB1 knockout had a significant disadvantage in vivo with respect to homing and growth in mice, compared to the control population. Taken together, we established a comprehensive workflow for CRISPR screen in PDX model of ALL in vivo. Our data identify and validate that CXCR4 and ITGB1 are required for homing and growth of PDX ALL cells in mice. Conclusion We show that CRISPR/Cas9 functional genetic screens are feasible in PDX acute leukemia models in vivo and report the first such screen, as far as to our knowledge. Extending CRISPR/Cas9 screens to patients' cells will greatly facilitate our understanding of individual leukemia biology and therapeutic targets in the future. Disclosures Becker: AVA Lifescience GmbH: Consultancy.

ANKHD1 Interacts with the Proapoptotic Protein SIVA and Plays a Role in the Proliferation and Stathmin Activation of Acute Leukemia Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2419-2419
Author(s):  
Joao Machado-Neto ◽  
Mariana Lazarini ◽  
Patricia Favaro ◽  
Paula de Melo Campos ◽  
Renata Scopim-Ribeiro ◽  
...  
Keyword(s):  
Cell Migration ◽  
Acute Leukemia ◽  
Tumor Growth ◽  
Chromosome Instability ◽  
Leukemia Cells ◽  
Alpha Tubulin ◽  
Functional Studies

Abstract Abstract 2419 Introduction: Acute leukemia and solid tumors result from alterations in the essential pathways of cell physiology including apoptosis, proliferation and genome instability. In solid tumors, the proapoptotic SIVA protein modulates apoptosis, proliferation, migration and promotes Stathmin inhibition through phosphorylation. Stathmin regulates microtubules dynamics and its hyperactivity confers chromosome instability in leukemia cells. Using two-hybrid system assay, we have identified SIVA as a binding partner of ANKHD1, an ankyrin-repeat-containing protein. ANKHD1 is overexpressed in acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) and has the potential role of regulating multiple cellular functions via their repeat motifs. We thus hypothesized that ANKHD1 and SIVA could be involved in leukemogenesis. We aimed to evaluate SIVA expression in normal and leukemia hematopoietic cells, to confirm the endogenous ANKHD1/SIVA association, and to investigate the functional role of both proteins in apoptosis, proliferation, migration, and Stathmin activation. Materials and Methods: Expression of SIVA was evaluated by qPCR in total bone marrow cells from 22 healthy donors, 42 AML and 21 ALL patients at diagnosis. All normal donors and patients provided informed written consent and the study was approved by the ethics committee of the Institution. Leukemia cell lines (Jurkat, Namalwa or U937 cells) were used for functional studies. Endogenous protein interaction was verified by immunopreciptation and cofocal microscopy. We stably knocked down the endogenous expression level of ANKHD1 or SIVA with specific shRNA-expressing lentiviral vector and in vitro apoptosis was examined by AnnexinV/PI, cell growth by MTT assay and colony formation, and migration by transwell assays. In addition, we investigated in vivo tumor growth; leukemia cells were implanted in the dorsal sub cutis of NOD/SCID mice and tumors were excised, measured and weighed after 15 days. Stathmin activation proteins (Stathmin, phospho-Stathmin, alpha tubulin and acetylated-alpha tubulin) and apoptotic proteins (BCL-XL, BAX, JNK and phospho-JNK) were evaluated by Western blot. Appropriated statistical analysis was performed. Results: SIVA expression was significantly decreased in AML and ALL cells compared with normal hematopoietic cells (P<0.05), a reverse pattern of ANKHD1 expression, when compared with published data. Immunopreciptation and confocal analyses confirmed that ANKHD1 and SIVA interact and co-localize in the cytoplasm of leukemia cells. Functional studies revealed that SIVA and ANKHD1 have antagonistic effects on migration, Stathmin activation, and in vivo tumor growth. SIVA silencing resulted in a significantly increased cell migration, Stathmin activation (decreased Stathmin phosphorylation), and augmented in vivo tumor growth (P<0.05). On the other hand, ANKHD1 silencing resulted in a significantly decreased cell migration, Stathmin inactivation (increased Stathmin phosphorylation and alpha tubulin acetylation), and reduced in vivo tumor growth (P<0.05). Regarding apoptosis and proliferation, SIVA knockdown resulted in a significant decrease in apoptosis response to UV and daunorubicin induction and a downregulation of proapoptotic proteins p-JNK and BAX, an upregulation of the antiapoptotic protein BCL-XL, but no modulation was observed in proliferation and clonal growth in vitro. In contrast, ANKHD1 knockdown resulted in a significant decrease of proliferation and clonogenicity (P<0.05), but no changes were observed in apoptosis in vitro. Conclusion: Our data indicate SIVA as a tumor suppressor gene in leukemia cells, and SIVA downmodulation may contribute to the apoptosis resistance and chromosome instability. ANKHD1 may be an oncogene, and the upregulation of this protein in leukemia cells might lead to increased proliferation and generate chromosomal instability through increased Stathmin activation. The results suggest that ANKHD1 inhibits SIVA and restoration of SIVA expression or inhibition of ANKHD1 may be an attractive approach in leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The cancer-testis antigen NXF2 is activated by the hypomethylating agent decitabine in acute leukemia cells in vitro and in vivo

2013 ◽  
Vol 8 (5) ◽  
pp. 1549-1555 ◽  
Author(s):  
JIHAO ZHOU ◽  
YONGHUI LI ◽  
YUSHI YAO ◽  
LIXIN WANG ◽  
LI GAO ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Leukemia Cells ◽  
Cancer Testis Antigen ◽  
Hypomethylating Agent ◽  
Cancer Testis

Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo

1995 ◽  
Vol 36 (2) ◽  
pp. 165-171 ◽  
Author(s):  
Sylvia A. Holden ◽  
Beverly A. Teicher ◽  
Michael F. Robinson ◽  
David Northey ◽  
Andre Rosowsky
Keyword(s):  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitors

scholarly journals A p53-MDM2 Interaction Inhibitor, DS-5272, Inhibits the Development of MLL-Fusion Leukemia with the Assistance of Tumor Immunity

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 796-796
Author(s):  
Susumu Goyama ◽  
Yasutaka Hayashi ◽  
XiaoXiao Liu ◽  
Shiori Shikata ◽  
Yosuke Tanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Tumor Immunity ◽  
P53 Protein ◽  
Leukemia Cells ◽  
Mouse Leukemia ◽  
Nsg Mice ◽  
P53 Activation

Abstract MLL-fusion leukemia is an aggressive form of leukemia carrying chimeric fusion of the MLL gene. Adverse therapy response of MLL-fusion leukemia is partly associated with the attenuated p53 response. The principal cellular antagonist of p53 is an E3 ubiquitin ligase MDM2. MDM2 binds to p53 and induces proteasomal degradation to downregulate p53 protein level. Therefore, targeting of p53-MDM2 interaction to reactivate p53 function is an attractive therapeutic approach for MLL-fusion leukemia. In this study, we assessed the effect of an orally active inhibitor of p53-MDM2 interaction, DS-5272, in a mouse leukemia model driven by MLL-AF9. DS-5272 inhibited in vitro growth of mouse leukemia cells transformed by MLL-AF9 with the IC50 value in the nanomolar range. A single administration of DS-5272 in vivo upregulated expression of p53 protein as well as its target genes, and induced cell cycle arrest, apoptosis, and differentiation of MLL-AF9 cells. Multiple oral doseadministration of DS-5272 (3 times per week) caused nearly complete tumor regressions of MLL-AF9 leukemia cells that were sustained well beyond the drug administration period with tolerable toxicity. In contrast, DS-5272 showed little effect on p53-deficient bone marrow cells transformed by MLL-AF9 both in vitro and in vivo, confirming that the antileukemic effect of DS-5272 is mediated by p53 activation. Despite the remarkable effect of DS-5272 against MLL-AF9 leukemia with wild-type p53, all mice eventually developed leukemia after a long latency, indicating the existence of leukemia stem cells (LSCs) that are resistant to p53 activation. The therapy-resistant LSCs were relatively enriched within the bone marrow (BM) endosteal region where osteoblasts reside. In contrast, LSCs in the BM central portion were eliminated almost completely by the DS-5272 treatment. Thus, LSCs within the osteoblast-rich area appear to be protected from p53-induced cell death. RNA-Seq analyses revealed the upregulation of inflammation- and interferon-associated genes in MLL-AF9 leukemia cells treated with DS-5272. Furthermore, DS-5272 treatment induced upregulation of PD-L1, a well-known suppressor of tumor immunity, in MLL-AF9 cells. These expression changes suggest that p53 activation triggered an immune-inflammatory response that led to leukemia regression. Interestingly, LSCs reside in the BM endosteal region expressed higher level of PD-L1 compared with those in the BM central portion, which may account for their low sensitivity to DS-5272. To examine the potential contribution of tumor immunity to the DS-5272-mediated suppression of leukemic growth, we next assessed the in vivo effect of DS-5272 on MLL-AF9 leukemia using immunodeficient NOD.Cg- Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice as recipients. Strikingly, the antileukemia effect of DS-5272 was markedly attenuated in NSG mice, indicating the important role of tumor immunity to enhance the efficacy of DS-5272. We then depleted PD-L1 in MLL-AF9 cells using the CRISPR/Cas9 system, and found that PD-L1-depleted MLL-AF9 cells become more sensitive to DS-5272 treatment. These data suggest that DS-5272 inhibits the development of MLL-AF9 leukemia with the assistance of tumor immunity, and its therapeutic efficacy is enhanced by PD-L1 inhibition in MLL-AF9 cells. In summary, our study demonstrated the potent antitumor activity of a p53-MDM2 interaction inhibitor, DS-5272, against MLL-fusion leukemia with intact p53. LSCs reside within the BM endosteal region express high level of PD-L1 and are relatively resistant to DS-5272 treatment. Combining p53-MDM2 inhibitors with the immune checkpoint inhibitors may result in synergistic enhancement of cell death and improved efficacy in the treatment of myeloid leukemia. Disclosures Kitamura: Daiichi Sankyo: Research Funding.

scholarly journals Identification of GPAT1 As a Novel Therapeutic Target for Acute Leukemia By Inhibiting Leukemia Specific Metabolism

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1384-1384
Author(s):  
Hidetoshi Irifune ◽  
Yu Kochi ◽  
Masayasu Hayashi ◽  
Yoshikane Kikushige ◽  
Toshihiro Miyamoto ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cell Lines ◽  
Mass Spectrometer ◽  
Mitochondrial Function ◽  
Therapeutic Target ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Leukemia Cell Lines

With the development of mass spectrometer technology, recent studies revealed the critical roles of cancer-specific metabolism for tumor propagation in several types of cancers. In leukemia, many studies have been conducted to elucidate a leukemia-specific metabolism, and several effective treatments such as IDH1/2 inhibitors targeting acute myeloid leukemia (AML) with IDH1/2 mutation have been developed. To identify the new metabolic pathways on which acute leukemia cells depend, we purified water-soluble metabolites from CD34+ hematopoietic stem and progenitor cells (HSPCs) of healthy donors, AML and acute lymphoblastic leukemia (ALL) patients, and we comprehensively measured 116 metabolites using mass spectrometer analysis. From this experiment, we found that the cellular content of glycerol 3-phosphate (G3P) in CD34+ AML and ALL cells was lower than that of normal CD34+ HSPCs. G3P is an intermediate metabolite in the glycolysis metabolic pathway and is utilized as a substrate for phospholipids synthesis. The initial and rate-limiting step of phospholipids synthesis is the synthesis of lysophosphatidic acid (LPA) from G3P and acyl-CoA mediated by glycerol 3-phosphate acyltransferases (GPATs). Since CD34+ acute leukemia cells contained significantly lower level of G3P, we hypothesized that leukemia cells actively consumed G3P and synthesized LPA by GPATs. GPATs are classified into four isoforms based on intracellular localization and substrate preference. GPAT1 and GPAT2 are mitochondrial GPATs that are localized to the mitochondrial outer membrane, but on the other hand, GPAT3 and GPAT4 are microsomal GPATs that are localized to the endoplasmic reticulum membrane, each encoded by independent genes. GPAT1 is identified as an essential gene for the growth of leukemia cells by RNAi screen analysis in the public database (DepMap). We found that CD34+ immature AML cells exhibited higher GPAT1 expression as compared to CD34- more differentiated AML cells and normal T cells. GPAT1 knockdown inhibited the proliferation of several acute leukemia cell lines including THP-1 and Kasumi-1 in vitro and in vivo. Moreover, a mitochondrial GPATs specific inhibitor (FSG67), which was originally developed as a drug to treat obesity and diabetes, suppressed the growth of the leukemia cell lines through the induction of G1 cell cycle arrest. Growth inhibition was rescued by exogenous administration of LPA, suggesting that the synthetic activity mediated by mitochondrial GPATs should be required for acute leukemia growth. Furthermore, FSG67 induced the apoptosis of leukemia cells derived from AML and ALL patients without affecting normal CD34+ HSPCs at least in vitro. We also confirmed that the injection of FSG67 resulted in the suppression of AML and ALL propagation in vivo using patient-derived xenograft models (see figure). GPAT1 regulates the mitochondrial function by producing LPA which is an essential metabolite for maintaining mitochondrial fusion. Actually, the amount of LPA was decreased in GPAT1 knockdown acute leukemia cells. We next examined mitochondrial energy production by extracellular flux assay, and found that GPAT1 knockdown as well as FSG67 significantly suppressed oxygen consumption rate of acute leukemia cells. Consistent with the impaired mitochondrial function, FSG67 suppressed the mitochondrial membrane potential, indicating that GPAT1 should play a pivotal role in maintaining leukemia-specific mitochondrial function. These results collectively suggest that the synthesis of LPA from G3P catalyzed by GPAT1 has a critical role in propagation of acute leukemia cells irrespective of their lineage origin. Thus, GPAT1 is a novel and common therapeutic target for human acute leukemia through suppressing leukemia-specific mitochondrial function. Figure Disclosures Akashi: Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding; Sumitomo Dainippon, Kyowa Kirin: Consultancy.

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