Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

Nieborowska‐Skorska, Margaret; Sullivan, Kathleen E.; Dasgupta, Yashodhara; Podszywałow-Bartnicka, Paulina; Hoser, Grazyna; Maifrede, Silvia; Martı́nez, Esteban; Marcantonio, Daniela Di; Bolton-Gillespie, Elisabeth; Cramer-Morales, Kimberly; Lee, Jae Woong; Li, Min; Słupianek, Artur; Gritsyuk, Daniel; Cerny-Reiterer, Sabine; Seferyńska, Ilona; Stokłosa, Tomasz; Bullinger, Lars; Zhao, Huaqing; Gorbunova, Vera; Piwocka, Katarzyna; Valent, Peter; Civin, Curt I.; Müschen, Markus; Dick, John E.; Wang, Jean; Bhatia, Smita; Bhatia, Ravi; Eppert, Kolja; Minden, Mark D.; Sykes, Stephen M.; Skórski, Tomasz

doi:10.1172/jci90825

Cited by 69 publications

(131 citation statements)

References 55 publications

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“…Our data carried out on primary AML blasts are in agreement with recent findings in immortalized solid tumor and leukemia cell lines, showing that PARP inhibition may increase FAS and DR5 transcript and protein levels [35]. In addition, Meng et al reported that exposure of AML blasts to olaparib at concentrations likely devoid of cytotoxic effects results in sensitization to the antiproliferative effects of recombinant TRAIL [35]. Herein, we show that olaparib as single agent directly inhibits AML cell proliferation and induces cell death.…”

Section: Discussionsupporting

confidence: 92%

The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-κB activation

et al. 2018

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Olaparib is a potent orally bioavailable poly(ADP-ribose) polymerase inhibitor (PARPi), approved for BRCA-mutated ovarian and breast cancers. We recently showed that olaparib at clinically achievable concentrations exerts anti-proliferative and pro-apoptotic effects in vitro as monotherapy against primary acute myeloid leukemia (AML) blasts, while sparing normal bone marrow (BM) hematopoietic cells. Since AML expresses low levels of death receptors that may contribute to apoptosis resistance, in this study we investigated whether the anti-leukemia activity of olaparib involves modulation of FAS and TRAIL receptors DR5 and DR4. Our data show that the primary AML samples tested express FAS and DR5 transcripts at levels lower than normal BM. In this context, apoptosis triggered by olaparib is associated with a dose-dependent up-regulation of death receptors expression and caspase 8 activation. Olaparib-mediated FAS up-regulation requires NF-κB activation, as indicated by the increase of p65 phosphorylation and decrease of IκBα. Moreover, FAS up-regulation is abrogated by pretreatment of AML cells with two different NF-κB inhibitors. These results indicate that NF-κB activation and consequent induction of death receptor expression contribute to the anti-leukemia effect of olaparib in AML.

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Section: Discussionsupporting

confidence: 92%

The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-κB activation

et al. 2018

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“…Therefore, these features support a conclusion that BCR-ABL induces a mutator phenotype [59]. Evidence that BRCA/DNA-PK-deficient CML leukemia stem cells are highly sensitive to inhibitors of poly-(ADP-ribose) polymerase 1 (PARP1) [60] brought about a potential of targeting key DNA repair enzymes in CML, which are in synthetic lethal relationship with BCR-ABL.signaling, reflecting responsiveness of BCR-ABL-positive myeloid cells to DNA damage following genotoxic treatment [41]. Some studies also addressed functionality of the ATM-Chk2 signaling axis in CML.…”

mentioning

confidence: 56%

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confidence: 57%

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

Stetka

Gurský

Velasquez

et al. 2020

Cancers

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Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions.CML is characterized by an indolent, chronic phase (CP) preceding an acute transformation to BC. Failure of DNA damage repair and loss or malfunction of DDR components accompanied by accumulation of DNA damage and genomic instability has been considered in CML evolution [38,39]. It was proposed that BCR-ABL-expressing cells feature reduced activation of the ATR-Chk1-mediated DDR signaling, with ensuing accumulation of substantial genomic instability due to replication stress and oxidative damage. Mechanistically, such disruption of ATR-dependent signaling was attributed to nuclear import of BCR-ABL after DNA damage and its binding to ATR [40]. However, contrasting data were also reported, showing that BCR-ABL does activate ATR-Chk1 signaling, reflecting responsiveness of BCR-ABL-positive myeloid cells to DNA damage following genotoxic treatment [41]. Some studies also addressed functionality of the ATM-Chk2 signaling axis in CML. Thus, c-Abl is a nuclear tyrosine kinase activated by DNA damage in an ATM-dependent manner [42,43]. Even though the BCR-ABL is predominantly localized to the cytoplasm [44], the aforementioned ability of BCR-ABL translocation to the nucleus after DNA damage led to a proposal that BCR-ABL and c-Abl share multiple protein interactions including that with ATM [40]. As a consequence, ATM-mediated activatory phosphorylation of Chk2 was detected in BCR-ABL-expressing cellular models and...

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“…Results represent mean ± SD percentage of living cells when compared to untreated cells from triplicates; * p < .025 in comparison to one drug treatment using Student’s t test. (D) HR activity in primary cells was examined as described before [14]. Cells (1–5 × 10 6 ) were co-transfected with 2 µg linearized plasmid carrying HR reporter cassette (HR event restores functional GFP expression) and 0.1 µg dsRedMito vector (for transfection efficiency) using a Human CD34 Cell Nucleofector ® Kit (Lonza) and Amaxa Nucleofector (Walkersville, MD) as described before [14].…”

Section: Figurementioning

confidence: 99%

“…(D) HR activity in primary cells was examined as described before [14]. Cells (1–5 × 10 6 ) were co-transfected with 2 µg linearized plasmid carrying HR reporter cassette (HR event restores functional GFP expression) and 0.1 µg dsRedMito vector (for transfection efficiency) using a Human CD34 Cell Nucleofector ® Kit (Lonza) and Amaxa Nucleofector (Walkersville, MD) as described before [14]. After 72 hours the percentage of GFP+/DsRed + cells in DsRed + cells was analyzed by flow cytometry (FACSCanto, BD Biosciences, San Jose, CA) to assess HR activity.…”

Section: Figurementioning

confidence: 99%

Drugging DNA repair to target T-ALL cells

Dasgupta

Golovine

Nieborowska‐Skorska

et al. 2017

Leukemia & Lymphoma

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Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

Cited by 69 publications

References 55 publications

The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-κB activation

The poly(ADP-ribose) polymerase inhibitor olaparib induces up-regulation of death receptors in primary acute myeloid leukemia blasts by NF-κB activation

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

Drugging DNA repair to target T-ALL cells

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