Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors

Ikeda, Daisuke; Chi, SungGi; Uchiyama, Satoshi; Nakamura, H.; Guo, Yong-Mei; Yamauchi, Nobuhiko; Yuda, Junichiro; Minami, Yosuke

doi:10.3390/ijms23115950

Cited by 15 publications

(15 citation statements)

References 163 publications

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“…Despite associating with good prognosis, NPM1-mutated cases were allocated to P1AML, probably due to the HOX gene upregulation in these patients. 20,21 The 24-miRNAs were involved in regulating stemness, differentiation, and proliferation, and our signature was enriched in cancer pathways. [22][23][24][25][26][27][28][29] Most underexpressed miRNAs functioned as tumour suppressors.…”

Section: Discussionmentioning

confidence: 98%

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A miRNA signature related to stemness identifies high‐risk patients in paediatric acute myeloid leukaemia

et al. 2023

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Despite the high survival rates, leukaemia remains the leading cause of death related to cancer in children. 1 Besides, treatment short-and long-term side effects hugely impact the survivors' and families' quality of life, 2 stressing the need to improve the current risk stratification of patients. Genetic aberrations at diagnosis and measurable residual disease (MRD) levels are used as prognostic biomarkers. 3 The stemness pathway, regulated by the NOTCH, WNT/βcatenin, HOX, and FLT3 pathways, among others, is often altered in leukaemia, 4,5 and high expression of stemnessrelated genes has been associated with poor outcomes in children and adult patients. Ng et al. developed a 17-gene leukaemic stem cell score (LSC17) to predict prognosis in adults with acute myeloid leukaemia (AML), 6 and Elsayed

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Section: Discussionmentioning

confidence: 98%

“…Alternatively, the miRNA signature could be a surrogate of their good‐risk underlying genetics. Despite associating with good prognosis, NPM1‐ mutated cases were allocated to P1AML, probably due to the HOX gene upregulation in these patients 20,21 …”

Section: Discussionmentioning

confidence: 99%

A miRNA signature related to stemness identifies high‐risk patients in paediatric acute myeloid leukaemia

et al. 2023

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“…The prognosis of BCR-ABL -mutated AML seems to depend on the cytogenetic and/or molecular background rather than BCR-ABL itself. Cases of AML with this mutation can be often challenging to distinguish from the presentation of CML in a blast crisis [ 49 , 50 , 51 ].…”

Section: Genetic Alterations In Amlmentioning

confidence: 99%

Association between Immunophenotypic Parameters and Molecular Alterations in Acute Myeloid Leukemia

et al. 2023

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Acute myeloid leukemia (AML) is a hematologic malignancy that occurs due to alterations such as genetic mutations, chromosomal translocations, or changes in molecular levels. These alterations can accumulate in stem cells and hematopoietic progenitors, leading to the development of AML, which has a prevalence of 80% of acute leukemias in the adult population. Recurrent cytogenetic abnormalities, in addition to mediating leukemogenesis onset, participate in its evolution and can be used as established diagnostic and prognostic markers. Most of these mutations confer resistance to the traditionally used treatments and, therefore, the aberrant protein products are also considered therapeutic targets. The surface antigens of a cell are characterized through immunophenotyping, which has the ability to identify and differentiate the degrees of maturation and the lineage of the target cell, whether benign or malignant. With this, we seek to establish a relationship according to the molecular aberrations and immunophenotypic alterations that cells with AML present.

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“…Acute myeloid leukemia (AML) is a highly heterogeneous incurable disease that is classified based on molecular and genetic alterations [ 1 ]. Mutations in the FMS-like tyrosine kinase 3 ( FLT3 ) gene are the most common mutations in AML [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

et al. 2023

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Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.

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Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors

Cited by 15 publications

References 163 publications

A miRNA signature related to stemness identifies high‐risk patients in paediatric acute myeloid leukaemia

A miRNA signature related to stemness identifies high‐risk patients in paediatric acute myeloid leukaemia

Association between Immunophenotypic Parameters and Molecular Alterations in Acute Myeloid Leukemia

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

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