FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome

Abstract

Oncogenic transformation of hematopoietic stem cells by chimeric fusion kinases causing constitutive activation of FGFR1 leads to a stem cell leukemia/lymphoma (SCLL) syndrome, accompanied by widespread dysregulation of gene activity. We now show that FGFR1 activation is associated with upregulation of MYC and pharmacological suppression of FGFR1 activation leads to downregulation of MYC and suppression of MYC target genes. Luciferase reporter assays demonstrate FGFR1 can directly regulate MYC expression and this effect is enhanced in the presence of chimeric FGFR1 kinases. In SCLL cells, a truncated form of FGFR1 is generated by granzyme B cleavage of the chimeric kinases, producing a nucleus-restricted derivative that can bind MYC regulatory regions. Mutation of the granzyme B cleavage site prevents relocation to the nucleus but does not suppress MYC activation, suggesting additional mechanisms of MYC activation in the presence of cytoplasm-restricted chimeric kinases. We show one of these mechanisms involves activating cytoplasmic STAT5, which upregulates MYC independent of the truncated FGFR1 kinase. Targeting MYC function using shRNA knockdown and 10054-F8 in SCLL cells leads to inhibition of cell proliferation and synergizes with the BGJ398 FGFR1 inhibitor, suggesting a combination therapy that could be used in the treatment of SCLL.

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

“…Activation of FGFR1 in SCLL implies a role for tyrosine phosphorylation of target proteins that is associated with leukemogenesis and indeed known targets of FGFR1 such as PLCG2 and SRC are activated . However, we have recently reported that the chimeric kinases seen in SCLL can be cleaved by granzyme B, to generate a truncated form of FGFR1, which is not phospho‐activated and which specifically translocates to the nucleus, where it is presumed to activate gene expression that contributes to the promotion of SCLL . We now demonstrate the relative contribution of the BCR STK domain in the development of SCLL, using transduction and transplantation experiments in syngeneic mice using mutant chimeric kinases .…”

“…Resistance to FGFR1 inhibitors, however, in model systems, occurs through mutation of the FGFR1 kinase and deletion of PTEN requiring alternative strategies . In various preclinical studies, we have shown the potential benefit of targeting SRC, PI3K, Notch, MYC, BCL2 and now SHP2 as a potential therapeutic strategy, either alone or more likely in combination with other critical pathways promoting SCLL. While SCLL is a relatively rare disease, our recent demonstration that up to 20% of de novo AML also overexpress FGFR1 and that FGFR1 inhibitors can suppress their growth in human xenografts in immunocompromised mice, suggesting that developing targeting strategies against the consequences of FGFR1 activation in AML may have a more widespread application .…”

“…6,16 However, we have recently reported that the chimeric kinases seen in SCLL can be cleaved by granzyme B, to generate a truncated form of FGFR1, which is not phospho-activated and which specifically translocates to the nucleus, where it is presumed to activate gene expression that contributes to the promotion of SCLL. 17 We now demonstrate the relative contribution of the BCR STK domain in the development of SCLL, using transduction and transplantation experiments in syngeneic mice using mutant chimeric kinases. 18 In these experiments, we formally demonstrate the requirement of the FGFR1 TK domain in SCLL development and that the STK domain contributes to aggressiveness of the disease.…”

mRNA Expression of FGFR1 as Potential Marker for Predicting Prognosis of Surgical Resection of Small Cell Lung Cancer may be better than Protein Expression and Gene Amplification

“…Nevertheless, the recent clinical trials and findings showed limited efficacy of FGFR-targeted therapy in multiple malignant tumors, suggesting that combination therapy may be essential to improve the EGFR1-amplified patient outcomes [35][36][37]. Golfmann et al postulated synergistic treatment effects in FGFR1/VEGFR1-positive breast cancer patients by dual targeting of FGFR and VEGFR [36].…”

Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation

“…Although TKI therapies have been used to traditionally treat certain hematopoietic cancers, their use has often resulted in drug resistance. Recently it was discovered that FGFR1 fusion kinases are associated with the upregulation of MYC, which drives SCLL (35). Targeting the MYC complex in addition to chemotherapy, and the approaches described here may also be therapeutically beneficial for patients with SCLL.…”