Acute lymphoblastic leukemia

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

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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.

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Acknowledgements

This work was supported by a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to JAB), a Leukemia & Lymphoma Society Scholar Award in Clinical Research (to JAB), the Else-Kröner Forschungskolleg (FS), German Research Foundation, SFB 1074 (KMD and LHM), ‘Förderkreis für Tumor- und Leukämiekranke Kinder Ulm’ and in part by the MD Anderson Cancer Center Support Grant CA016672. STR DNA fingerprinting was done by the Cancer Center Support Grant-funded Characterized Cell Line core, NCI # CA016672. We are grateful for access to the data assembled by the ImmGen Consortium.

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Correspondence to J A Burger.

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Competing interests

JAB received research funding from Portola Pharmaceuticals and GPC is employee and shareholder of Portola Pharmaceuticals.

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This work was presented, in part, in oral sessions at the 2013 annual meeting of the American Society of Hematology (ASH) in New Orleans and at the 2014 annual meeting of the American Society of Hematology (ASH) in San Francisco.

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Köhrer, S., Havranek, O., Seyfried, F. et al. Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition. Leukemia 30, 1246–1254 (2016) doi:10.1038/leu.2016.9

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