Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia.
Intensified and central nervous system (CNS)-directed chemotherapy has improved outcomes for pediatric B cell acute lymphoblastic leukemia (B-ALL) but confers treatment-related morbidities. Moreover, many patients suffer relapses, underscoring the need to develop new molecular targeted B-ALL therapies. Using a mouse model, we show that leukemic B cells require pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo for survival and proliferation. In diagnostic samples from human pediatric and adult B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small-molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated the growth of 69 B-ALL samples in vitro, including high-risk (HR) subtypes. Orally administered fostamatinib reduced heavy disease burden after xenotransplantation of HR B-ALL samples into immunodeficient mice and decreased leukemia dissemination into spleen, liver, kidneys, and the CNS of recipient mice. Thus, SYK activation sustains the growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Tatiana
T
Perova
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Ildiko
I
Grandal
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Lauryl M J
LM
Nutter
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Eniko
E
Papp
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Irina R
IR
Matei
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
Joseph
J
Beyene
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Paul E
PE
Kowalski
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Johann K
JK
Hitzler
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario M5T 2M9, Canada.
Mark D
MD
Minden
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Cynthia J
CJ
Guidos
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. jayne.danska@sickkids.ca.
Jayne S
JS
Danska
D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines; D009154:Mutation; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D010078:Oxazines / Q000737:chemistry; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D012008:Recurrence; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology*; D000072377:Syk Kinase; D016896:Treatment Outcome
C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib