رسالة جامعية
FLT3-mutant leukemia: Signaling adaptation and novel mouse models
| العنوان: | FLT3-mutant leukemia: Signaling adaptation and novel mouse models |
|---|---|
| المؤلفون: | Bruner, Joshua Kyle |
| المساهمون: | Friedman, Alan, Small, Donald, Park, Ben, Pratilas, Christine |
| بيانات النشر: | Johns Hopkins University USA |
| سنة النشر: | 2017 |
| المجموعة: | Johns Hopkins University, Baltimore: JScholarship |
| مصطلحات موضوعية: | FLT3, ERK signaling, MEK inhibition, adaptive resistance |
| الوصف: | Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation of myeloid precursor cells. While karyotype is understood to be the most important prognostic factor in AML, approximately 45% of patients present with normal karyotype, necessitating more refined prognostic criteria. Genetic mutations provide for further classification, and many mutations, including those in NPM1, CEBPA, RUNX1, and FLT3, have been shown to affect disease outcome. Among these mutations with prognostic significance, the internal tandem duplication in FLT3 (FLT3/ITD) is observed with the highest frequency in patients and confers poor prognosis. Given the prevalence and significance of FLT3/ITD in AML, FLT3 tyrosine kinase inhibitors (TKIs) are being actively pursued as a therapeutic strategy for patients with FLT3/ITD AML, however clinical responses remain limited. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. We identified a reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated, and the anti-leukemia effects were more pronounced compared to either drug alone. These studies reveal an adaptive feedback mechanism in FLT3/ITD AML associated with reactivation of ERK signaling in response to TKI therapy. In addition to FLT3/ITD, a second mutation in FLT3 occurs in 7% of patients and consists of a point mutation in the kinase domain, usually at position D835. This kinase domain mutation (FLT3/TKD) results in constitutive activation of the receptor and activation of downstream signaling. However, unlike FLT3/ITD, FLT3/TKD has little to no prognostic significance. Previous work has shown that FLT3/ITD-driven disease results in a more aggressive phenotype compared with FLT3/TKD. In addition, FLT3/ITD strongly ... |
| نوع الوثيقة: | thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | http://jhir.library.jhu.edu/handle/1774.2/60807Test |
| الإتاحة: | http://jhir.library.jhu.edu/handle/1774.2/60807Test |
| رقم الانضمام: | edsbas.CE8A5808 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |