scholarly journals Pim kinase inhibitor co-treatment decreases alternative non-homologous end-joining DNA repair and genomic instability induced by topoisomerase 2 inhibitors in cells with FLT3 internal tandem duplication

Oncotarget ◽  
2021 ◽  
Vol 12 (18) ◽  
pp. 1763-1779
Author(s):  
Mario Scarpa ◽  
Shivani Kapoor ◽  
Eric S. Tvedte ◽  
Kshama A. Doshi ◽  
Ying S. Zou ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Tandem Duplication ◽  
Kinase Inhibitor ◽  
End Joining ◽  
Internal Tandem Duplication ◽  
Topoisomerase 2 ◽  
Non Homologous End Joining ◽  
Flt3 Internal Tandem Duplication ◽  
In Cells

scholarly journals AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

Blood ◽  
2014 ◽  
Vol 123 (6) ◽  
pp. 905-913 ◽  
Author(s):  
Erika K. Keeton ◽  
Kristen McEachern ◽  
Keith S. Dillman ◽  
Sangeetha Palakurthi ◽  
Yichen Cao ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Internal Tandem Duplication ◽  
Rna Translation ◽  
Key Points ◽  
Messenger Rna Translation ◽  
Flt3 Internal Tandem Duplication

Key Points AZD1208 is a selective pan-Pim kinase inhibitor with efficacy in AML cells, xenografts, and Flt3-internal tandem duplication or Flt3 wild-type patient samples. AML cell growth inhibition is associated with suppression of p70S6K, 4EBP1 phosphorylation, and messenger RNA translation.

A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 885-887 ◽  
Author(s):  
Mark Levis ◽  
Kam-Fai Tse ◽  
B. Douglas Smith ◽  
Elizabeth Garrett ◽  
Donald Small
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitor ◽  
Internal Tandem Duplication ◽  
Flt3 Internal Tandem Duplication ◽  
Study Dose ◽  
Acute Myeloid

Abstract Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML.

Thymocyte Selection-Associated High-Mobility Group Box Protein (TOX) Induces Genomic Instability in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 475-475
Author(s):  
Riadh Lobbardi ◽  
Jordan Pinder ◽  
Barbara Martinez-Pastor ◽  
Jessica S Blackburn ◽  
Nouran Abdelfattah ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Strand Break ◽  
End Joining ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Non Homologous End Joining

Abstract MYC and NOTCH are major oncogenic drivers in T-cell Acute Lymphoblastic Leukemia (T-ALL), yet additional collaborating genetic lesions likely collaborate to induce frank malignancy. To identify these factors, a large-scale transgenic screen was completed where 38 amplified and over-expressed genes found in human T-ALL were assessed for accelerating leukemia onset in the zebrafish transgenic model. From this analysis, Thymocyte selection-associated homeobox protein (TOX) synergized with both MYC and NOTCH to induce T-ALL. TOX is dynamically regulated in T cell development with peak expression occurring when thymocytes are actively undergoing T cell receptor (TCR) recombination. TOX is best known for regulating the specification of the mature CD4+ T cells. Despite TOX being genomically amplified in a subset of human and mouse T-ALL and being overexpressed in 100% of human T-ALL, a role for TOX in regulating leukemogenesis has not been reported. Characterization of zebrafish T-ALLs revealed that TOX expands the overall number of malignant T-ALL clones and promoted genomic instability as assessed by changes in DNA content. To identify TOX binding partners, antibody immunoprecipitation studies were performed followed by Tandem Mass Spectrometry. TOX was found to interact with KU70/KU80 but not other DNA repair enzymes including LigaseIV, DNA-PKC, or XRCC4. These results were verified by Western blot analysis and reciprocal immunoprecipitation studies using antibodies specific to KU70/KU80 both in the absence and presence of DNAseI treatment. Given that TOX elevated genomic instability in the zebrafish model and bound specifically to KU70/KU80 – the initiating factors required for Non-Homologous End Joining (NHEJ) repair - we hypothesized that TOX is a negative regulator of double-strand break repair. Fluorescent repair assays were completed in 3T3 fibroblasts and confirmed that TOX inhibits Non-Homologous End Joining (NHEJ). Both the nuclear localization signal and HMG-box were required for the ability of TOX to inhibit double-strand break repair. Dynamic real-time imaging studies confirmed that TOX suppresses recruitment of fluorescent-tagged KU70 to DNA breaks. Importantly, TOX loss of function increased NHEJ in human T-ALL cells and reduced time to DNA repair as assessed by fluorescent Traffic Light Reporter assays and quantitative assessment of 53BP1 and γH2A.X foci resolution following irradiation. Given the prominent role TOX has in T cell development and its coordinated regulation during active TCRβ and TCRα rearrangement, it is likely that the normal function of TOX is to transiently suppress the NHEJ pathway during Recombination-Activating Gene (RAG)-mediated recombination. Prolonging the time to DNA repair would likely facilitate long-range repair across VDJ segments. In the setting of T-ALL, TOX is aberrantly re-activated, thereby suppressing KU70/KU80 function to promote genomic instability and ultimately elevating rates at which acquired mutations and rearrangements are amassed in developing pre-malignant T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer’s Achilles’ Heel

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1392
Author(s):  
Daniele Caracciolo ◽  
Caterina Riillo ◽  
Maria Teresa Di Martino ◽  
Pierosandro Tagliaferri ◽  
Pierfrancesco Tassone
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Precision Oncology ◽  
End Joining ◽  
Cancer Hallmarks ◽  
Promising Target ◽  
Non Homologous End Joining

Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.

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