Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

Lee, Erwin M.; Yee, Dean Y.; Busfield, Samantha J.; McManus, J. F.; Cummings, Nicholas James; Vairo, Gino; Wei, Andrew H.; Ramshaw, Hayley S.; Powell, Jason A.; Lopez, Angel F.; Lewis, Ian D.; McCall, Martin N.; Lock, Richard B.

doi:10.3324/haematol.2014.113092

Cited by 54 publications

(41 citation statements)

References 48 publications

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“…This antibody potently induces antibody-dependent cell-mediated cytotoxicity (ADCC) of AML blasts and LSCs in vitro and effectively depletes cell types highly expressing CD123, such as plasmacytoid dendritic cells and basophils, without affecting pluripotent progenitors/stem cells [79]. Furthermore, CSL362 administration to NGS mice xenografted with primary human AML cells consistently increased the antileukemic effect elicited by the administration of the drug combination cytarabine/daunorubicin [80].…”

Section: Cd123 (Il3rα)mentioning

confidence: 97%

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

Pelosi

Castelli

Testa

2015

Blood Cells, Molecules, and Diseases

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Section: Cd123 (Il3rα)mentioning

confidence: 97%

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

Pelosi

Castelli

Testa

2015

Blood Cells, Molecules, and Diseases

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“…Patient-derived AMLs were described previously (27). The mouse bone marrow stromal cell line MS-5 was kindly provided by Prof. Mori (Niigata University, Niigata, Japan; ref.…”

Section: In Vitro Dose Response Assaysmentioning

confidence: 99%

“…MS-5 cells were seeded into 96-well plates at 10 4 cells per well in aMEM supplemented with 10% FBS, penicillin/streptomycin, and L-glutamine (2 mmol/L), and grown to confluence over 3 to 4 days. Human AML PDX cells (27) were retrieved from cryostorage and seeded onto the confluent MS-5 monolayer at 5 Â 10 4 cells per well in Iscove's modified Dulbecco's medium containing 0.5% FBS, 1% penicillin/streptomycin, and L-glutamine. The next day, dinaciclib was added to duplicate wells at concentrations between 5 nmol/L and 10 mmol/L and plates were incubated for an additional 24 hours.…”

Section: In Vitro Dose Response Assaysmentioning

confidence: 99%

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

et al. 2016

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Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclibinduced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. Cancer Res; 76(5); 1158-69. Ó2015 AACR.

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“…[28][29][30] Mutations affecting KIT D816, DMNT3A R882, FLT3-TKD D835/I836, IDH1 R132, IDH2 R140/R172, JAK1 T478/V623, JAK2 V617, KRAS G12/13, MPL W515, NPM1 W288, and NRAS G12/13 and Q61 were detected using a multiplexed matrix-assisted laser desorption/ionization time-of-flight genotyping approach (Sequenom MassARRAY Compact System) as previously described. 30 Constructs and mRNA analysis Details of construct generation, RNA-Seq of MP-A08-treated cells, bioinformatics, and quantitative reverse transcription polymerase chain reaction (RT-PCR) are presented in the supplemental Methods (available on the Blood Web site).…”

Section: Mutation Analyses Of Aml Biopsiesmentioning

confidence: 99%

“…30 Briefly, mice were sublethally irradiated (275 cGy) 24 hours prior to IV injection of 5-10 3 10 6 primary human AML cells via tail vein. Engraftment levels were quantified by flow cytometry and expressed as the percentage of human CD45 Immunohistochemistry on mouse bone marrow was performed as previously described 33 with human mitochondrial antibodies (Abcam).…”

Section: Xenotransplantationmentioning

confidence: 99%

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

Powell

Lewis

Zhu

et al. 2017

Blood

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Key Points• Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspasedependent cell death.• SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patientderived xenografts of AML.Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34 1 progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML. (Blood. 2017;129(6):771-782)

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Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

Cited by 54 publications

References 48 publications

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

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