FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells
Abstract
Abstract Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored toward eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FMS-like tyrosine kinase 3 (FLT3) is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knockout (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3–internal tandem duplication (ITD)-mutated but not FLT3–wild-type AMLs resulted in short-term leukemic grafts of FLT3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from the fetal liver, cord blood, and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD-positive LSCs are eradicated upon FLT3 deletion whereas HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes.
Article Details
Authors (22)
Joana L. Araújo
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Elvin Wagenblast
Veronique Voisin
Jessica McLeod
Olga I. Gan
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Suraj Bansal
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Liqing Jin
Amanda Mitchell
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Blaise Gratton
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Sarah Cutting
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Andrea Arruda
Princess Margaret Cancer Centre, University Health Network
Monica Doedens
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Anthea Travas
10Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Dennis Kim
1Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
Jose-Mario Capo-Chichi
2University Health Network, Advanced Molecular Diagnostics Laboratory, Toronto, Canada
Sagi Abelson
Mark D. Minden
Princess Margaret Cancer Centre, University Health Network
Jean C. Y. Wang
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Manuel A. Sobrinho-Simões
2Department of Hematology, Centro Hospitalar Universitário de São João, Porto, Portugal
Perpétua Pinto-do-Ó
4Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
Eric Lechman
2University of Pittsburgh, Pittsburgh, United States
John E. Dick