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FLT3 突变的白血病干细胞：耐药机制与新治疗靶点

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets.

作者信息

Capelli Debora

机构信息

Department of Hematology, Azienda Ospedaliera Universitaria, Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy.

出版信息

Cancers (Basel). 2024 May 10;16(10):1819. doi: 10.3390/cancers16101819.

DOI:10.3390/cancers16101819
PMID:38791898
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11119130/
Abstract

Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML.

摘要

尽管一线和二线有靶向药物可用，但只有30%的FLT3突变急性髓系白血病（AML）患者能被治愈。在多种耐药机制中，FLT3突变白血病干细胞（LSC）的耐药机制因其代谢和基因组特征而最难根除。糖原合成的重新激活、RAS/丝裂原活化蛋白激酶（MAPK）通路的抑制以及FLT3的降解可能有助于对抗LSC对FLT3抑制剂（FLT3i）的耐药性。LSC还具有CD34+/CD25+/CD123+/CD99+免疫表型的特征。FLT3的受体和配体、自然杀伤细胞2成员D配体（NKGD2L）以及CD123是嵌合抗原受体T细胞（CAR-T）、双特异性T细胞衔接分子（BiTEs）、CAR自然杀伤细胞（CAR-NK）和本文最近设计并报道的纳米颗粒的一些靶点。这些新治疗方案的联合应用，有望采用微小残留病（MRD）驱动的方法，为治疗FLT3突变AML的挑战提供未来的解决方案。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/2553bccab00d/cancers-16-01819-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/6359b60c0fdb/cancers-16-01819-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/470c256b6198/cancers-16-01819-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/2553bccab00d/cancers-16-01819-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/6359b60c0fdb/cancers-16-01819-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/470c256b6198/cancers-16-01819-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7fd/11119130/2553bccab00d/cancers-16-01819-g003.jpg

相似文献

[1]
FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets.

Cancers (Basel). 2024-5-10

[2]
Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones.

J Hematol Oncol. 2016-7-27

[3]
A novel approach for relapsed/refractory FLT3 acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib.

Mol Cancer. 2022-3-4

[4]
A Leukemia-Associated CD34/CD123/CD25/CD99+ Immunophenotype Identifies FLT3-Mutated Clones in Acute Myeloid Leukemia.

Clin Cancer Res. 2015-5-8

[5]
Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.

Cancers (Basel). 2022-9-2

[6]
A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL.

J Immunother Cancer. 2022-3

[7]
Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells.

J Hematol Oncol. 2018-5-2

[8]
Characterization of FLT3-ITD acute myeloid leukemia: molecular profiling of leukemic precursor cells.

Blood Cancer J. 2020-8-25

[9]
Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia.

J Hematol Oncol. 2022-11-5

[10]
Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues.

Stem Cells Transl Med. 2020-11

引用本文的文献

[1]
Tracking Response and Resistance in Acute Myeloid Leukemia through Single-Cell DNA Sequencing Helps Uncover New Therapeutic Targets.

Int J Mol Sci. 2024-9-17

本文引用的文献

[1]
The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and aurora kinases.

Leuk Lymphoma. 2024-11

[2]
LAIR-1 agonism as a therapy for acute myeloid leukemia.

J Clin Invest. 2023-11-15

[3]
Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia.

Oncogene. 2023-11

[4]
Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.

Genome Biol. 2023-8-31

[5]
Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease.

J Hematol Oncol. 2023-8-17

[6]
Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.

Blood Adv. 2023-10-24

[7]
Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions.

Cancers (Basel). 2023-4-15

[8]
The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and Aurora kinases.

Res Sq. 2023-2-22

[9]
Leukemic stem cells and therapy resistance in acute myeloid leukemia.

Haematologica. 2023-2-1

[10]
GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells.

Med Oncol. 2022-12-8

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