TY - JOUR
T1 - FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice
AU - Bailey, Emily
AU - Li, Li
AU - Duffield, Amy S.
AU - Ma, Hayley S.
AU - Huso, David L.
AU - Small, Don
PY - 2013/12/24
Y1 - 2013/12/24
N2 - FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately one third of acute myeloid leukemia cases. The most common FLT3 mutations in acute myeloid leukemia are internal tandem duplication (ITD) mutations in the juxtamembrane domain (23%) and point mutations in the tyrosine kinase domain (10%). The mutation substituting the aspartic acid at position 838 (equivalent to the human aspartic acid residue at position 835) with a tyrosine (referred to as FLT3/D835Y hereafter) is the most frequent kinase domain mutation, converting aspartic acid to tyrosine. Although both of these mutations constitutively activate FLT3, patients with an ITD mutation have a significantly poorer prognosis. To elucidate the mechanisms behind this prognostic difference, we have generated a knock-in mouse model with a D838Y point mutation in FLT3 that corresponds to the FLT3/D835Y mutation described in humans. Compared with FLT3/ITD knock-in mice, the FLT3/D835Y knock-in mice survive significantly longer. The majority of these mice develop myeloproliferative neoplasms with a less-aggressive phenotype. In addition, FLT3/D835Y mice have distinct hematopoietic development patterns. Unlike the tremendous depletion of the hematopoietic stem cell compartment we have observed in FLT3/ITD mice, FLT3/D835Y mutant mice are not depleted in hematopoietic stem cells. Further comparisons of these FLT3/ D835Y knock-in mice with FLT3/ITD mice should provide an ideal platform for dissecting the molecular mechanisms that underlie the prognostic differences between the two different types of FLT3 mutations.
AB - FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately one third of acute myeloid leukemia cases. The most common FLT3 mutations in acute myeloid leukemia are internal tandem duplication (ITD) mutations in the juxtamembrane domain (23%) and point mutations in the tyrosine kinase domain (10%). The mutation substituting the aspartic acid at position 838 (equivalent to the human aspartic acid residue at position 835) with a tyrosine (referred to as FLT3/D835Y hereafter) is the most frequent kinase domain mutation, converting aspartic acid to tyrosine. Although both of these mutations constitutively activate FLT3, patients with an ITD mutation have a significantly poorer prognosis. To elucidate the mechanisms behind this prognostic difference, we have generated a knock-in mouse model with a D838Y point mutation in FLT3 that corresponds to the FLT3/D835Y mutation described in humans. Compared with FLT3/ITD knock-in mice, the FLT3/D835Y knock-in mice survive significantly longer. The majority of these mice develop myeloproliferative neoplasms with a less-aggressive phenotype. In addition, FLT3/D835Y mice have distinct hematopoietic development patterns. Unlike the tremendous depletion of the hematopoietic stem cell compartment we have observed in FLT3/ITD mice, FLT3/D835Y mutant mice are not depleted in hematopoietic stem cells. Further comparisons of these FLT3/ D835Y knock-in mice with FLT3/ITD mice should provide an ideal platform for dissecting the molecular mechanisms that underlie the prognostic differences between the two different types of FLT3 mutations.
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U2 - 10.1073/pnas.1310559110
DO - 10.1073/pnas.1310559110
M3 - Article
C2 - 24255108
AN - SCOPUS:84891356597
SN - 0027-8424
VL - 110
SP - 21113
EP - 21118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -