We have made significant progress during the prior funding period in assessing the role of FLT3mutations in AMI, and the development of murine models to test FLT3 inhibitors. These haveincluded analysis of FLT3-ITD expression alone, and in combination with cooperating alleles suchas PML-RARalpha. Working with Project 1, Project 2 has been instrumental in preclinicaldevelopment of FLT3 inhibitors by showing efficacy in murine models of disease, resulting in PhaseI and Phase II trials of two different FLT3 inhibitors in Project 5. We plan to move forward withadditional studies of the role of FLT3-ITD in leukemogenesis using conditional knock-in alleles.
In Specific Aim 1, we will analyze the in vivo activity of FLT3-ITD and activation loop alleles, and try tounderstand the relative predilection of FLT3-ITD for myeloid lineage disease, and of FLT3 activationloop alleles for lymphoid disease. We will use high speed multiparameter flow cytometry to test thehypothesis that these alleles have differential effect on cell fate determination at the multipotentprogenitor stage (LMPP/MPP) where FLT3 is highly expressed during hematopoietic development.We will study the mechanism whereby FLT3-ITD, in contrast with FLT3 WT, is a potent activator ofSTATS using mutations in the context of FLT3 that abrogate this activity.
In Specific Aim 2, we willexplore cooperating effects of these accurate genotypic models of FLT3-ITD mediated diseasethrough crosses with several complementing alleles including, C/EBPalpha, and MLL fusions,working with Projects 3 and 4. These in turn will serve as useful in vivo models for testing novelcombination therapies that are developed in Project 1. We .will also pursue recent findingssuggesting that retroviral FLT3-ITD retroviral integration sites may contribute to pathogenesis ofAML in the Cathepsin G - PML-RARalpha model of cooperativity.
In Specific Aim 3, we willdevelop murine models of myeloproliferative disease (MPD) mediated by the JAK2V617F allele thatwe and others have recently identified.. Finally, we will use murine models of MPD as a platform fortesting novel JAK2 inhibitors for development of clinical trials in Project 5. Overall, this is a highlyinteractive Project that will build on a proven track record of success and preclinical development ofnovel therapies for myeloid malignancies.
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