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Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia)

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 17392

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Special Issue Editor

Prof. Dr. Maria Paola Martelli

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Guest Editor

Hematology and Clinical Immunology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Interests: acute leukemia; AML; gene mutation; NPM1; FLT3; epigenetic genes; leukemogenesis; drug screening; drug treatment; targeted therapy

Special Issue Information

Dear Colleagues,

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene occur in about 30% of all acute myeloid leukemia (AML) patients. These mutations include internal tandem duplication (ITD) of the juxtamembrane domain (more frequent) and point mutations in the tyrosine kinase domain (TKD), both leading to constitutive activation of the protein kinase. Whilst FLT3-ITD mutations confer undoubtedly poor prognosis with higher risk of relapse and lower survival rate, the role of FLT3-TKD mutations still remains unclear.

FLT3 mutations are gatekeeper mutations in AML and, as demonstrated in different murine models, play a key role as co-operative mutation in AML development. This makes FLT3 mutation a valid target for therapy.

Several FLT3 inhibitors have been developed and are in clinical use in patients with FLT3-mutated AML, with midostaurine, FDA-approved as first-line treatment in association with chemotherapy, and gilteritinib, FDA-approved as single agent in relapsed/refractory AML with FLT3 mutations. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and toxicity. A variety of clinical studies are exploring the safety and efficacy of different FLT3-inhibitors in either novel combinations or sequential therapies.

Growing evidence indicates that FLT3 mutation status may change during the disease course as a manifestation of clonal evolution of the disease, with AML either acquiring or losing the mutation. Therefore, testing and re-testing for FLT3 mutations become essential at diagnosis and relapse for the establishment of the most proper therapeutic strategy.

With this Special Issue, we kindly invite our colleagues to submit their latest research findings, reviews or perspectives covering either biological or clinical aspects of FLT3 mutations in AML. The topics may include new knowledge on pathways involved in leukemogenesis, as well as description of in vitro and in vivo FLT3-mutated AML models. Clinical significance of FLT3 mutations in AML and related debated issues are invited to be addressed. Additionally, papers either describing the established therapeutic role or discussing the open questions on the clinical use of FLT3 inhibitors are welcome. We believe this Special Issue may offer insights onto relevant biological and clinical issues on FLT3 mutations in AML and targeted therapy, while providing new perspectives on patients management and future therapeutic approaches.

We look forward to your contributions and will be happy to discuss your suggestions.

Prof. Dr. Maria Paola Martelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

AML
FLT3
leukemogenesis
murine models
cell signaling
targeted therapy
minimal residual disease (MRD)
drug resistance
relapse
clonal evolution

Published Papers (5 papers)

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Research

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19 pages, 5690 KiB

Open AccessArticle

Hsa_circ_0015278 Regulates FLT3-ITD AML Progression via Ferroptosis-Related Genes

by Jiquan Jiang, Jing Feng, Xiangnan Song, Qing Yang, Hongbo Zhao, Rui Zhao, Xinrui He, Yaoyao Tian, Lianjie Wang and Yanhong Liu

Cancers 2023, 15(1), 71; https://doi.org/10.3390/cancers15010071 - 22 Dec 2022

Cited by 5 | Viewed by 2126

Abstract

AML with the FLT3-ITD mutation seriously threatens human health. The mechanism by which circRNAs regulate the pathogenesis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. Differentially expressed circRNAs and mRNAs were identified from multiple integrated data sources. The target miRNAs and mRNAs of the circRNAs were predicted using various databases. The PPI network, ceRNA regulatory network, GO, and KEGG enrichment analyses were performed. The “survival” and the “pROC” R packages were used for K-M and ROC analysis, respectively. GSEA, immune infiltration analysis, and clinical subgroup analysis were performed. Finally, circRNAs were validated by Sanger sequencing and qRT-PCR. In our study, 77 DECircs-1 and 690 DECircs-2 were identified. Subsequently, 11 co-up-regulated DECircs were obtained by intersecting DECircs-1 and DECircs-2. The target miRNAs of the circRNAs were screened by CircInteractome, circbank, and circAtlas. Utilizing TargetScan, ENCORI, and miRWalk, the target mRNAs of the miRNAs were uncovered. Ultimately, 73 FerRGs were obtained, and the ceRNA regulatory network was constructed. Furthermore, MAPK3 and CD44 were significantly associated with prognosis. qRT-PCR results confirmed that has_circ_0015278 was significantly overexpressed in FLT3-ITD mutant-type AML. In summary, we constructed the hsa_circ_0015278/miRNAs/FerRGs signaling axis, which provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation. Full article

(This article belongs to the Special Issue Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia))

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12 pages, 920 KiB

Open AccessArticle

Prognostic Relevance of NPM1 and FLT3 Mutations in Acute Myeloid Leukaemia, Longterm Follow-Up—A Single Center Experience

by Erika Borlenghi, Chiara Cattaneo, Diego Bertoli, Elisa Cerqui, Silvana Archetti, Angela Passi, Margherita Oberti, Tatiana Zollner, Carlotta Giupponi, Chiara Pagani, Nicola Bianchetti, Chiara Bottelli, Samuele Bagnasco, Margherita Sciumè, Alessandra Tucci and Giuseppe Rossi

Cancers 2022, 14(19), 4716; https://doi.org/10.3390/cancers14194716 - 28 Sep 2022

Cited by 4 | Viewed by 1518

Abstract

The prognosis of acute myeloid leukemia depends on genetic aberrations, particularly NPM1 and FLT3-ITD mutations. The targeted drugs’ availability has renewed interest in FLT3 mutations, but the impact of these genetic alterations using these treatments is yet to be confirmed. Our objective was to evaluate the results obtained with the intensified NILG-AML 01/00 protocol (ClinicalTrials.gov Identifier: NCT 00400673) in 171 unselected patients (median age, 54.5 years, range 15–74) carrying the FLT3 (ITD or TKD) and/or NPM1 mutations. The CR rate and 5-y survival were 88.3% and 58% +/− 4, respectively, significantly higher in the NPM1-mutated (CR 93.9%, p: 0.0001; survival 71% +/− 6, p: 0.0017, respectively). In isolated ITD patients, the CR was lower (66.7%, p: 0.0009), and the 3 years-relapse-free survival worse (24%, p: <0.0002). The presence of ITD, irrespective of the allelic ratio, or TKD mutation, did not significantly affect the survival or relapse-free survival among the NPM1-co-mutated patients. Our data indicate that a high dose of ARAC plus idarubicin consolidation exerts a strong anti-leukemic effect in NPM1-mutated patients both with the FLT3 wild-type and mutated AML, while in the NPM1 wild-type and FLT3-mutated, the therapeutic effect remains unsatisfactory. New strategies incorporating target therapy with second-generation inhibitors will improve these results and their addition to this aggressive chemotherapeutic program merits testing. Full article

(This article belongs to the Special Issue Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia))

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Review

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16 pages, 786 KiB

Open AccessReview

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

by Kateryna Fedorov, Abhishek Maiti and Marina Konopleva

Cancers 2023, 15(8), 2312; https://doi.org/10.3390/cancers15082312 - 15 Apr 2023

Cited by 7 | Viewed by 4514

Abstract

FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia. Two broad categories of FLT3 mutations are ITD and TKD, with the former having substantial clinical significance. Patients with FLT3-ITD mutation present with a higher disease burden and have inferior overall survival, due to high relapse rates after achieving remission. The development of targeted therapies with FLT3 inhibitors over the past decade has substantially improved clinical outcomes. Currently, two FLT3 inhibitors are approved for use in patients with acute myeloid leukemia: midostaurin in the frontline setting, in combination with intensive chemotherapy; and gilteritinib as monotherapy in the relapsed refractory setting. The addition of FLT3 inhibitors to hypomethylating agents and venetoclax offers superior responses in several completed and ongoing studies, with encouraging preliminary data. However, responses to FLT3 inhibitors are of limited duration due to the emergence of resistance. A protective environment within the bone marrow makes eradication of FLT3^mut leukemic cells difficult, while prior exposure to FLT3 inhibitors leads to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling, promoting resistance to currently available therapies. Multiple novel therapeutic strategies are under investigation, including BCL-2, menin, and MERTK inhibitors, as well as FLT3-directed BiTEs and CAR-T therapy. Full article

(This article belongs to the Special Issue Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia))

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14 pages, 308 KiB

Open AccessReview

Target Therapy for Extramedullary Relapse of FLT3-ITD Acute Myeloid Leukemia: Emerging Data from the Field

by Andrea Duminuco, Cinzia Maugeri, Marina Parisi, Elisa Mauro, Paolo Fabio Fiumara, Valentina Randazzo, Domenico Salemi, Cecilia Agueli, Giuseppe Alberto Palumbo, Alessandra Santoro, Francesco Di Raimondo and Calogero Vetro

Cancers 2022, 14(9), 2186; https://doi.org/10.3390/cancers14092186 - 27 Apr 2022

Cited by 5 | Viewed by 2541

Abstract

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in FLT3, as well known, represent the most common genomic alteration in acute myeloid leukemia (AML), identified in approximately one-third of newly diagnosed adult patients. In recent years, this has represented an important therapeutic target. Drugs such as midostaurin, gilteritinib, and sorafenib, either alone in association with conventional chemotherapy, play a pivotal role in AML therapy with the mutated FLT3 gene. A current challenge lies in treating forms of AML with extramedullary localization. Here, we describe the general features of myeloid sarcoma and the ability of a targeted drug, i.e., gilteritinib, approved for relapsed or refractory disease, to induce remission of these extramedullary leukemic localizations in AML patients with FLT3 mutation, analyzing how in the literature, there is an important development of cases describing this promising potential for care. Full article

(This article belongs to the Special Issue Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia))

16 pages, 1540 KiB

Open AccessReview

Role of Biomarkers in FLT3 AML

by Nitika, Jiao Wei and Ai-Min Hui

Cancers 2022, 14(5), 1164; https://doi.org/10.3390/cancers14051164 - 24 Feb 2022

Cited by 16 | Viewed by 5663

Abstract

Acute myeloid leukemia is a disease characterized by uncontrolled proliferation of clonal myeloid blast cells that are incapable of maturation to leukocytes. AML is the most common leukemia in adults and remains a highly fatal disease with a five-year survival rate of 24%. More than 50% of AML patients have mutations in the FLT3 gene, rendering FLT3 an attractive target for small-molecule inhibition. Currently, there are several FLT3 inhibitors in the clinic, and others remain in clinical trials. However, these inhibitors face challenges due to lack of efficacy against several FLT3 mutants. Therefore, the identification of biomarkers is vital to stratify AML patients and target AML patient population with a particular FLT3 mutation. Additionally, there is an unmet need to identify alternative approaches to combat the resistance to FLT3 inhibitors. Here, we summarize the current knowledge on the utilization of diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for FLT3-mutated AML. The resistance mechanisms to various FLT3 inhibitors and alternative approaches to combat this resistance are also discussed and presented. Full article

(This article belongs to the Special Issue Targeting FLT3 Mutations in AML (Acute Myeloid Leukemia))

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