The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (...
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-09-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/9/9/121 |
| id |
doaj-44ba12fc53cc44f4bfefaad86deddafa |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Etai Adam Hye Na Kim Eun Ji Gang Caitlin Schnair Solomon Lee Solah Lee Sajad Khazal Osanna Kosoyan Marina Konopleva Chintan Parekh Deepa Bhojwani Alan S. Wayne Hisham Abdel-Azim Nora Heisterkamp Yong-Mi Kim |
| spellingShingle |
Etai Adam Hye Na Kim Eun Ji Gang Caitlin Schnair Solomon Lee Solah Lee Sajad Khazal Osanna Kosoyan Marina Konopleva Chintan Parekh Deepa Bhojwani Alan S. Wayne Hisham Abdel-Azim Nora Heisterkamp Yong-Mi Kim The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL Cancers ALL PI3K drug resistance CAM-DR idelalisib migration mouse model leukemia |
| author_facet |
Etai Adam Hye Na Kim Eun Ji Gang Caitlin Schnair Solomon Lee Solah Lee Sajad Khazal Osanna Kosoyan Marina Konopleva Chintan Parekh Deepa Bhojwani Alan S. Wayne Hisham Abdel-Azim Nora Heisterkamp Yong-Mi Kim |
| author_sort |
Etai Adam |
| title |
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL |
| title_short |
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL |
| title_full |
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL |
| title_fullStr |
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL |
| title_full_unstemmed |
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL |
| title_sort |
pi3kδ inhibitor idelalisib inhibits homing in an in vitro and in vivo model of b all |
| publisher |
MDPI AG |
| series |
Cancers |
| issn |
2072-6694 |
| publishDate |
2017-09-01 |
| description |
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL. |
| topic |
ALL PI3K drug resistance CAM-DR idelalisib migration mouse model leukemia |
| url |
https://www.mdpi.com/2072-6694/9/9/121 |
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doaj-44ba12fc53cc44f4bfefaad86deddafa2020-11-24T22:36:32ZengMDPI AGCancers2072-66942017-09-019912110.3390/cancers9090121cancers9090121The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALLEtai Adam0Hye Na Kim1Eun Ji Gang2Caitlin Schnair3Solomon Lee4Solah Lee5Sajad Khazal6Osanna Kosoyan7Marina Konopleva8Chintan Parekh9Deepa Bhojwani10Alan S. Wayne11Hisham Abdel-Azim12Nora Heisterkamp13Yong-Mi Kim14Department of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USADepartment of Pediatrics, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USAThe quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL.https://www.mdpi.com/2072-6694/9/9/121ALLPI3Kdrug resistanceCAM-DRidelalisibmigrationmouse modelleukemia |