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Nature. 2015 May 21;521(7552):357-61. doi: 10.1038/nature14231. Epub 2015 Mar 23.

Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.

Author information

1
Department of Laboratory Medicine, University of California, San Francisco, California 94143, USA.
2
Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
3
Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
4
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10466, USA.
6
Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Philadelphia 19104, USA.
7
University of New Mexico Cancer Center, Albuquerque, New Mexico 87102, USA.
8
Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
9
Pediatric Hematology-Oncology, University of California, San Francisco, California 94143, USA.
10
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033, USA.
11
Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
12
Autoimmunity and Functional Genomics Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
13
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2M9, Canada.
14
Department of Anatomy, University of California, San Francisco, California 94143, USA.
15
Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany.
16
BIOSS Centre for Biological Signalling Studies and Faculty of Biology, Albert-Ludwigs-Universität Freiburg, and MPI of Immunbiologie and Epigenetics, 79104 Freiburg, Germany.

Abstract

B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

PMID:
25799995
PMCID:
PMC4441554
DOI:
10.1038/nature14231
[Indexed for MEDLINE]
Free PMC Article

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