Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib

Ko, Ya Chen; Hu, Chung-Yi; Liu, Zheng Hau; Tien, Hwei‐Fang; Ou, Da-Liang; Chien, Hsiung–Fei; Lin, Liang-In

doi:10.3390/ijms20051230

Cited by 7 publications

(5 citation statements)

References 60 publications

(77 reference statements)

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“…The apoptotic effect of AraC is p53-dependent, since the FLT3-ITD leukemia cell line, which harbors mutant TP53, is AraC-resistant ( Ko et al, 2019 ). Perhaps AraC-induced autophagy is also p53-dependent.…”

Section: Discussionmentioning

confidence: 99%

Acceleration of slow autophagy flux induced by arabinofuranosyl cytidine improves its antileukemic effectiveness in M-NFS-60 cells

FOUAD¹,

ELSOKKARY²,

SHAKOR³

2022

Turkish Journal of Biology

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Arabinofuranosyl cytidine (AraC) is an analog of deoxycytidine used as an anticancer drug for leukemic patients. The effective dose always produces severe complications. The present study investigated the modulation of autophagy and its impact on the cytotoxicity of AraC toward murine myelogenous leukemia cells (M-NFS-60). Autophagy was inhibited by NH 4 Cl or Bafilomycin A1 or enhanced by amino acid starvation, glucose starvation, mild hyperthermia (41 °C), or rapamycin (Rap). Cells were treated with different concentrations, 0 to 2 μM, of AraC in the presence or absence of autophagy modulators. AraC-induced apoptosis is combined with autophagy, especially at lower concentrations. This autophagy is characterized by a slow flux, as indicated by levels of LC3B II and P62 proteins. Inhibition of autophagy did not alter cleaved caspase 3 levels (c-casp.3) or cell viability measured by MTT assays. Conversely, acceleration of AraC-induced autophagy by co-treatment with autophagy inducers reduced cell viability and increased c-casp.3 and c-PARP levels. Further, c-PARP levels were reduced in the presence of caspase inhibitor, Z-VAD-FMK. Enhancement of slow autophagic flux induced by low concentrations of AraC significantly increased the cytotoxicity of AraC toward M-NFS-60 cells. Such coadministration of autophagy inducers might improve the efficacy of AraC treatment and reduce effective doses.

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Section: Discussionmentioning

confidence: 99%

Acceleration of slow autophagy flux induced by arabinofuranosyl cytidine improves its antileukemic effectiveness in M-NFS-60 cells

FOUAD¹,

ELSOKKARY²,

SHAKOR³

2022

Turkish Journal of Biology

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“…Although the removal of Ara-C results in a slight increase in STAT5 phosphorylation, the resistance of MV4-11R cells to this drug is not directly linked to overactivated STAT5. ERK1/2 and AKT kinases that also play a crucial role in cell survival, are involved in the resistance of MV4-11 cells to Ara-C [29]. It is then likely that Ara-C depletion may overexpress or overactivate these survival pathways in resistant MV4-11 cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells

Brachet-Botineau

Deynoux

Vallet

et al. 2019

Cancers

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Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells.

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“…Upregulation of MCL-1 has been shown in different cell lines with varying FLT3-ITD IS at the JMD (MOLM-13, MV4-11) or TKD1 level (32D, A627E variant) compared to FLT3 wildtype (RS4-11) [33]. Upregulated MCL-1 at the protein level was also detected in a cytarabine-resistant cell line MV4-11-R harboring the FLT3-ITD mutation at the JMD level [93]. In the FLT3-ITD variant A627E inserting at the TKD1 level, Breitenbuecher et al described upregulation of anti-apoptotic MCL-1 and showed sustained activation of ERK1/2 despite midostaurin-mediated inhibition of FLT3.…”

Section: Characterizing the Molecular Basis Of Chemotherapy And Tki R...mentioning

confidence: 93%

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

Haage

Schraven

Mougiakakos

et al. 2023

Cancers

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Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches.

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Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib

Cited by 7 publications

References 60 publications

Acceleration of slow autophagy flux induced by arabinofuranosyl cytidine improves its antileukemic effectiveness in M-NFS-60 cells

Acceleration of slow autophagy flux induced by arabinofuranosyl cytidine improves its antileukemic effectiveness in M-NFS-60 cells

A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

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