<i>TET2</i> and <i>DNMT3A</i> Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors

Maifrede, Silvia; Le, Bac Viet; Nieborowska‐Skorska, Margaret; Golovine, Konstantin; Sullivan-Reed, Katherine; Dunuwille, Wangisa M.B.; Nacson, Joseph; Hulse, Michael; Keith, Kelsey; Madžo, Jozef; Caruso, Lisa Beatrice; Gazze, Zachary; Lian, Zhaorui; Padella, Antonella; Chitrala, Kumaraswamy Naidu; Bartholdy, Boris; Matławska-Wasowska, Ksenia; Marcantonio, Daniela Di; Simonetti, Giorgia; Greiner, Georg; Sykes, Stephen M.; Valent, Peter; Paietta, Elisabeth; Tallman, Martin S.; Fernandez, Hugo F.; Litzow, Mark R.; Minden, Mark D.; Huang, Jian; Martinelli, Giovanni; Vassiliou, George S.; Tempera, Italo; Piwocka, Katarzyna; Johnson, Neil; Challen, Grant A.; Skórski, Tomasz

doi:10.1158/0008-5472.can-20-3761

Cited by 34 publications

(37 citation statements)

References 58 publications

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“…In particular, the co-occurrence of FLT3 -ITD and TET2 mutations exacerbated the sensitivity of Lin − CD34 + primary AML cells to olaparib. On the contrary, cells expressing FLT3 -ITD alteration alone or in combination with DNMT3A mutations were resistant to the treatment with the inhibitor [ 135 ]. In line with data form primary samples, mouse models expressing activated-tyrosine kinases ( FLT3 -ITD, JAK2 V617F , MPL W515L , NRA S G12D ) showed that Tet2 -deficient cells were sensitive to PARPi, while Dnmt3a -deficient cells were not.…”

Section: Synthetic Lethality and Parp Inhibitors: A New Therapeutic W...mentioning

confidence: 99%

“…Seminal results, that will drive future development, are expected from the combination of PARPi with decitabine (NCT02878785), particularly in the sub-cohort of TET2 and TET2/DNMT3A -mutant AML for their high sensitivity to DNA damage [ 135 ], and from target-restricted studies in IDH1 / 2 mutant (NCT03953898) and in cohesin mutant (NCT03974217) AML. The preclinical evidence reported in IDH1 / 2 [ 142 , 143 , 156 ] or cohesin-mutated AML patients [ 140 , 155 ], as well as other subgroups, seems to promise success for molecularly directed trial designs for PARPi single agent and combination regimens.…”

Section: Clinical Activity Of Parp Inhibitors In Acute Leukemiamentioning

confidence: 99%

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Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

et al. 2022

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The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

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Section: Synthetic Lethality and Parp Inhibitors: A New Therapeutic W...mentioning

confidence: 99%

Section: Clinical Activity Of Parp Inhibitors In Acute Leukemiamentioning

confidence: 99%

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

et al. 2022

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“…It remains to be seen whether a similar association between PARP1 and TET1 exists in myeloid neoplasms. Conversely, somatic TET2 deficiency is a common feature of hematologic malignancies and is associated with downregulation of BRCA1 and LIG4, leading to impaired HR and NHEJ, respectively [ 214 ]. Thus, TET2-deficient cells are increasingly reliant on the PARP1-mediated alt-EJ DNA repair pathway, conferring sensitivity to PARPi therapy both in vitro and in vivo [ 214 , 215 ].…”

Section: Parp Inhibitors For the Treatment Of Myeloid Neoplasmsmentioning

confidence: 99%

“…Conversely, somatic TET2 deficiency is a common feature of hematologic malignancies and is associated with downregulation of BRCA1 and LIG4, leading to impaired HR and NHEJ, respectively [ 214 ]. Thus, TET2-deficient cells are increasingly reliant on the PARP1-mediated alt-EJ DNA repair pathway, conferring sensitivity to PARPi therapy both in vitro and in vivo [ 214 , 215 ]. In this manner, TET2 mutations may serve as a biomarker for PARPi sensitivity in epigenetically dysregulated malignancies.…”

Section: Parp Inhibitors For the Treatment Of Myeloid Neoplasmsmentioning

confidence: 99%

PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Csizmar

Saliba

Swisher

et al. 2021

Cancers

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Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.

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“…DSBs are among the most lethal DNA aberrations, and are repaired through either homologous recombination (HR) mediated repair or non-homologous end joining (NHEJ) ( 23 ). Targeting DNA repair pathways for cancer therapy has gained a momentum over the past few years, with poly(adenosine 5’-diphosphate-ribose) polymerase (PARP) inhibition for HR deficient tumors have shown promise in clinical settings ( 27–29 ). Therefore, identifying molecular regulation of DNA repair pathways important for AML cell survival is essential for developing effective combination targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

Boila

Ghosh

Bandyopadhyay

et al. 2022

Preprint

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Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. AML exhibits epigenetic deregulation and transcriptional plasticity that contributes to pathogenesis. KDM6 proteins are histone-3 lysine-27 demethylases that play major context dependent roles in AML evolution and therapy resistance. Here, we demonstrate that KDM6 demethylase function critically regulates DNA damage repair (DDR) gene expression programs in AML. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress, with deficiency of KDM6A (UTX) and KDM6B (JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations have been implicated in chemoresistance, although a significant percentage of relapsed AML have upregulated KDM6A. Based on these mechanistic findings, olaparib treatment significantly reduced engraftment of patient-derived xenografts. Thus KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6A loss was accompanied with a downregulated BCL2A1, which is commonly associated with venetoclax resistance. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying acquired KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity, and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

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TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors

Cited by 34 publications

References 58 publications

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

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