Critical individual roles of the BCR and FGFR1 kinase domains in BCR‐FGFR1‐driven stem cell leukemia/lymphoma syndrome

• Published in: International journal of cancer Vol. 146; no. 8; pp. 2243 - 2254
• Main Authors: Chong, Yating, Liu, Yun, Lu, Sumin, Cai, Baohuan, Qin, Haiyan, Chang, Chang‐Sheng, Ren, Mingqiang, Cowell, John K., Hu, Tianxiang
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.04.2020; Wiley Subscription Services, Inc
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; BCR protein; Cancer; Cell Transformation, Neoplastic; Cell viability; Chromosome translocations; Clonal deletion; Drug Synergism; Female; FGFR1; Fibroblast growth factor receptor 1; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Kinases; Leukemia; Leukemia - drug therapy; Leukemia - genetics; Leukemia - metabolism; Leukemia - pathology; Leukemogenesis; Lymphoma; Lymphoma - drug therapy; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Medical research; Mice; Mice, Inbred BALB C; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - pharmacology; Piperidines - administration & dosage; Piperidines - pharmacology; Protein Domains; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein-serine/threonine kinase; Protein-tyrosine kinase; Proto-Oncogene Proteins c-bcr - biosynthesis; Proto-Oncogene Proteins c-bcr - genetics; Proto-Oncogene Proteins c-bcr - metabolism; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Receptor, Fibroblast Growth Factor, Type 1 - biosynthesis; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; serine–threonine kinase; SHP2; Stem cell leukemia; Stem cells; tyrosine kinase; SHP2; leukemia; serine-threonine kinase; tyrosine kinase; FGFR1
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32665

Constitutive activation of FGFR1, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The BCR‐FGFR1 variant is unique in that the BCR component contributes a serine–threonine kinase (STK) to the N‐terminal end of the chimeric FGFR1 kinase. We have deleted the STK domain and mutated the critical Y177 residue and demonstrate that the transforming activity of these mutated genes is reduced compared to the BCR‐FGFR1 parental kinase. In addition, we demonstrate that deletion of the FGFR1 tyrosine kinase domain abrogates transforming ability, which is not compensated for by BCR STK activity. Unbiased screening for proteins that are inactivated as a result of loss of the BCR STK identified activated S6 kinase and SHP2 kinase. Genetic and pharmacological inhibition of SHP2 function in SCLL cells expressing BCR‐FGFR1 in vitro leads to reduced viability and increased apoptosis. In vivo treatment of SCLL in mice with SHP099 leads to suppression of leukemogenesis, supporting an important role for SHP2 in FGFR1‐driven leukemogenesis. In combination with the BGJ398 FGFR1 inhibitor, cell viability in vitro is further suppressed and acts synergistically with SHP099 in vivo suggesting a potential combined targeted therapy option in this subtype of SCLL disease. What's new? Constitutive activation of FGFR1 tyrosine kinase, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The relative contribution of the fusion partner genes remains unclear, however. Here, the authors show that the BCR gene serine–threonine kinase can modify disease course in vivo, through activation of SHP2 and its downstream targets. Pharmacologically targeting both SHP2 and FGFR1 displays synergistic efficacy in treating BCR‐FGFR1 disease subtype. The study indicates the potential role of fusion partner genes in modifying disease phenotype and rationalizes the need for precision therapeutics that target activation of both FGFR1 and fusion partners.