The impact of FLT3 mutations on treatment response and survival in Chinese <i>de novo</i> AML patients

Qiu, Qiao‐Cheng; Wang, Chao; Bao, Xiebing; Yang, Jing; Shen, Hongjie; Ding, Zixuan; Liu, Hong; He, Jun; Yao, Hong; Chen, Suning; Li, Zheng; Xue, Sheng‐Li; Liu, Song‐Bai

doi:10.1080/10245332.2017.1372248

Cited by 8 publications

(7 citation statements)

References 33 publications

(41 reference statements)

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“…The three main groups of mutated FLT3 hematopoietic cells include FLT3-ITDs, and also FLT3-point mutations in the juxtamembrane domain, and the tyrosine kinase domain mutations. FLT3-TKD-mutated AML patients have a more favorable prognosis clinically when compared with patients with FLT3-ITD mutations [13]. As such, an essentially significant degree of heterogeneity is found within the complex phenomenon of FLT3-mutated hematopoietic progenitor cell populations considered and is contributory to AML leukemogenesis.…”

Section: Multi-componentsmentioning

confidence: 96%

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

Agius¹

2017

BJSTR

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Section: Multi-componentsmentioning

confidence: 96%

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

Agius¹

2017

BJSTR

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“…Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that is aberrantly expressed in 70-100% of AML [7]. FLT3-internal tandem duplications (FLT3-ITD) mutation is the most common type of mutation affecting 25-30% of AML patients [8,9], including 5-15% pediatric patients [10]. AML cells with FLT3-ITD mutation are characterized by constitutive auto-phosphorylation and factor-independent activation of FLT3 receptors that enhance irregular cell proliferation through various signaling pathways including PI3K/AKT, Ras/MAPK and STAT [11,12].…”

Section: Introductionmentioning

confidence: 99%

GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells

Xia

Feng

et al. 2022

Preprint

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Glycogen Synthase Kinase-3 (GSK-3) was recently implicated in the dysregulated biology of acute myeloid leukemia (AML). Low concentrations of GSK-3 inhibitors, SB216763 and BIO, suppressed the proliferation of AML cells with FLT3-ITD as early as 24 h after treatment. BIO was used in subsequent assays since it exhibited higher inhibitory effects than SB216763. BIO induced G1 cell cycle arrest by regulating the expression of cyclin D2 and p21 in MV4-11 cells, and promoted apoptosis by regulating the cleaved-caspase3 and AKT signaling pathways. In vivo assays demonstrated that BIO suppressed tumor growth, while metabolomics assay showed that BIO reduced the levels of ATP and pyruvate in MV4-11 cells suggesting that it inhibited glycolysis. BIO markedly suppressed cell growth and induced apoptosis of AML cells with FLT3-ITD by partially inhibiting glycolysis, suggesting that BIO may be a promising therapeutic candidate for AML.

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“…Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that involves the uncontrolled clonal proliferation of blasts in the bone marrow and peripheral blood. It is characterized by clonal evolution and genetic heterogeneity [1][2][3]. Since cytogenetic profiles have become important indicators of prognosis in AML, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have incorporated certain cytogenetic and molecular abnormalities in AML classifications and risk stratifications.…”

Section: Introductionmentioning

confidence: 99%

“…Internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) mutations have been categorized as poor prognostic factors. FLT3 gene mutations occur in about 30% of adult patients diagnosed with AML, but in pediatric patients, it is rare and occurs at a rate of 5-15% [1]. FLT3-ITD triggers the activation of tyrosine kinase receptors and downstream signaling, leading to increased leukemic stem and progenitor cell proliferation and their increased survival [4].…”

Section: Introductionmentioning

confidence: 99%

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

et al. 2020

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Background: Acute myeloid leukemia (AML) with internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with poor outcomes. This study aimed to analyze the outcomes of pediatric AML patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era. Methods: We retrospectively reviewed and identified 18 patients diagnosed with non-M3 AML with FLT3-ITD mutations at Seoul National University Children's Hospital between May 2008 and August 2019. Results: The median age was 13 years (range, 6-19 yr). The median follow-up time was 43 months (range, 6-157 mo). Fourteen patients received BH-AC-based (N4-Behenoy1-1-β-D-arabinofuranosy1cytosine) and 4 received cytarabine-based induction chemotherapy. Complete remission (CR) was achieved in 72.2% of the patients after the first induction chemotherapy and 80% of the patients achieved CR after salvage therapy. The overall CR rate was 94% (17/18 patients). These 17 patients underwent hematopoietic stem cell transplantation (9 matched unrelated donors, 5 matched related donors, and 3 haploidentical donors). Relapse occurred in 22% of the patients. Event free survival and overall survival rates were 53.8±12.1% and 53.6±12.1%, respectively, and they were not significantly different according to the type of induction chemotherapy (P=0.690) or the type of donor (P=0.102). Conclusion: This study outlines the outcomes of pediatric AML patients with FLT3-ITD-mutations in one institution over a decade. Outcomes were significantly improved in this study compared to our previous report in 2004, where RFS and EFS were 0%. This study can provide baseline data for pediatric patients in the pre-FLT3 inhibitor era.

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The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients

Cited by 8 publications

References 33 publications

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

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