Asset Details
Do you wish to reserve the book?
FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia
Do you wish to request the book?
FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia
2024
Overview
Internal tandem duplication mutations in
fms-like tyrosine kinase 3
(
FLT3-ITD
) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the
FLT3
-
ITD
clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3.
FLT3-ITD
and loss-of-function mutations in
EZH2
are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine
Flt3-ITD
AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of
FLT3-ITD
leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for
FLT3-ITD
AML.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/91
/ 64/60
/ 82/29
/ 82/58
/ 96/106
/ 96/31
/ Animals
/ fms-Like Tyrosine Kinase 3 - genetics
/ fms-Like Tyrosine Kinase 3 - therapeutic use
/ Humans
/ Kinases
/ Leukemia
/ Leukemia, Myeloid, Acute - drug therapy
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - metabolism
/ Medicine
/ Mice
/ Mutation
/ Oncology
/ Polycomb Repressive Complex 2 - genetics
/ Protein Kinase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - therapeutic use
/ Protein-Tyrosine Kinases - genetics
/ Tyrosine
