Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition

• Published in: Leukemia 2016-06, Vol.30 (6), p.1246-1254
• Main Authors: Köhrer, S, Havranek, O, Seyfried, F, Hurtz, C, Coffey, G P, Kim, E, ten Hacken, E, Jäger, U, Vanura, K, O'Brien, S, Thomas, D A, Kantarjian, H, Ghosh, D, Wang, Z, Zhang, M, Ma, W, Jumaa, H, Debatin, K-M, Müschen, M, Meyer, L H, Davis, R E, Burger, J A
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 38/109; 38/39; 42/41; 45/61; 631/67/1990/283/2125; 631/80/86; 82/80; 96/1; 96/63; Acute lymphoblastic leukemia; AKT protein; Animal models; Animals; Antibodies; Antigens; B-cell receptor; Cancer; Cancer Research; Cell Line; Cell receptors; Cellular signal transduction; Critical Care Medicine; Development and progression; Forkhead Box Protein O1 - metabolism; FOXO1 protein; Gene expression; Genetic aspects; Health aspects; Hematology; Heterografts; Humans; Immunoglobulins; Intensive; Internal Medicine; Kinases; Leukemia; Lymphatic leukemia; Lymphocytes B; Lymphomas; Medicine; Medicine & Public Health; Mice; Myc protein; Oncology; original-article; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cells, B-Lymphoid - chemistry; Precursors; Properties; Protein-tyrosine kinase; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Antigen, B-Cell - metabolism; Signal Transduction; Signaling; Spleen; Syk Kinase - metabolism; Syk protein; Therapeutic applications; Therapeutic targets; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.9

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.