title: Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition.
abstract: Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: S
authors: S
authors: Köhrer
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: O
authors: O
authors: Havranek
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: F
authors: F
authors: Seyfried
authors: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.|Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: C
authors: C
authors: Hurtz
authors: Portola Pharmaceuticals, South San Francisco, CA, USA.
authors: G P
authors: GP
authors: Coffey
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: E
authors: E
authors: Kim
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: E
authors: E
authors: Ten Hacken
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors: U
authors: U
authors: Jäger
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors: K
authors: K
authors: Vanura
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: S
authors: S
authors: O'Brien
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: D A
authors: DA
authors: Thomas
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: H
authors: H
authors: Kantarjian
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: D
authors: D
authors: Ghosh
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Z
authors: Z
authors: Wang
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: M
authors: M
authors: Zhang
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: W
authors: W
authors: Ma
authors: Department of Immunology, Ulm University, Ulm, Germany.
authors: H
authors: H
authors: Jumaa
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: K-M
authors: KM
authors: Debatin
authors: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
authors: M
authors: M
authors: Müschen
authors: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors: L H
authors: LH
authors: Meyer
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: R E
authors: RE
authors: Davis
authors: Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: J A
authors: JA
authors: Burger
mesh_terms: D000818:Animals; D002460:Cell Line; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000737:chemistry*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase