Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas.

Stem cell leukemia/lymphoma syndrome (SCLL) is driven by constitutive activation of chimeric FGFR1 kinases generated by chromosome translocations. We have shown that FGFR inhibitors significantly suppress leukemia and lymphoma development in vivo, and cell viability in vitro. Since resistance to targeted therapies is a major reason for relapse, we developed FGFR1-overexpressing mouse and human cell lines that are resistant to the specific FGFR inhibitors AZD4547 and BGJ398, as well as non-specific inhibitors, such as ponatinib, TKI258 and E3810. Two mutually exclusive mechanisms for resistance were demonstrated; an activating V561M mutation in the FGFR1 kinase domain and mutational inactivation of PTEN resulting in increased PI3K/AKT activity. Ectopic expression of PTEN in the PTEN-mutant cells resensitizes them to FGFR inhibitors. Treatment of resistant cells with BGJ398, in combination with the BEZ235 PI3K inhibitor, shows an additive effect on growth in vitro and prolongs survival in xenograft models in vivo. These studies provide the first direct evidence for both the involvement of the FGFR1 V561M mutation and PTEN inactivation in the development of resistance in leukemias overexpressing chimeric FGFR1. These studies also provide a potential strategy to treat leukemias and lymphomas driven by FGFR1 activation that become resistant to FGFR1 inhibitors.

The black and white truth about domestic violence.

The radiological findings of child abuse have been a focus of radiological education. Intimate partner violence (IPV) is a significant health burden; however, this is not frequently illustrated in the radiology literature. Health care providers play a crucial role in screening, treating, and preventing future acts of domestic violence. Radiologists in particular are in a unique position in cases of domestic violence, unbiased by interaction with the victim and potentially the abuser. Head and neck injuries are the most common; however, any part of the body is at risk for injury in cases of domestic violence. Fostering awareness of domestic violence and familiarizing radiologists with the most common imaging findings of IPV can help these specialists make the proper diagnosis and improve patient care.

SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models.

Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines. Three newly developed pan-FGFR inhibitors, AZD4547, BGJ398 and JNJ42756493, show a significantly improved efficacy over the more established FGFR inhibitors, PD173074 and TKI258. To examine whether targeting FGFR1 suppresses leukemogenesis in de novo AML in vivo, we created xenografts in immunocompromized mice from primary, de novo AML that showed > 3-fold increased expression of FGFR1. Using BGJ398, the most potent inhibitor identified in the in vitro studies, AML progression in these mice was significantly suppressed compared with vehicle treated animals and overall survival improved. Importantly, no difference in disease course or survival was seen in AML xenografts that did not show overexpression of FGFR1. These observations support the idea that FGFR1 is a driver oncogene in de novo, FGFR1-overexpressing AML and that molecularly targeted therapies using FGFR1 inhibitors may provide a valuable therapeutic regimen for all FGFR1-overexpressing AML.