FLT3-mutant leukemia: Signaling adaptation and novel mouse models
Embargo until
2019-05-01
Date
2017-03-21
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Johns Hopkins University
Abstract
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 activates STAT5 signaling, while FLT3/TKD results in minimal STAT5 activity. This work points to STAT5 signaling as a key driver of the differential impact of these activating mutations, however existing models are ill equipped to accurately address this hypothesis. Therefore, we generated novel mouse models of FLT3-driven leukemia to better understand the role STAT5 signaling plays in the context of FLT3/ITD or FLT3/TKD. These models will allow for extensive study of FLT3- mutated leukemia in the presence or absence of STAT5 signaling, enabling a more complete understanding of the differences between the two types of FLT3 mutations.
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Keywords
FLT3, ERK signaling, MEK inhibition, adaptive resistance