Transcriptional alteration of DNA repair genes in Philadelphia chromosome negative myeloproliferative neoplasms

Kirschner, Martin; Bornemann, Anne; Schubert, Claudia; Gezer, Deniz; Kricheldorf, Kim; Isfort, Susanne; Brümmendorf, Tim H.; Schemionek, Mirle; Chatain, Nicolas; Skórski, Tomasz; Koschmieder, Steffen

doi:10.1007/s00277-019-03836-2

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…The disruption of MYC targets is also noteworthy, since MYC impairs myeloid differentiation and promotes the proliferation and survival of hematopoietic stem cells and multipotent progenitors to drive myeloproliferative neoplasms [21]. Additionally, some of the DEGs involved in repair mechanisms that were upregulated have been described as altered in MPN patients, such as ATM (human ortholog of worm atm-1), BARD1 (brd-1), BRCA1 (brc-1), RFC3 (rfc-3), and several members of the MSH (him-14, msh-5) gene families [22,23].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Guijarro-Hernández

Eder-Azanza

Hurtado

et al. 2023

Cells

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There is growing evidence that Ph-negative myeloproliferative neoplasms (MPNs) are disorders in which multiple molecular mechanisms are significantly disturbed. Since their discovery, CALR driver mutations have been demonstrated to trigger pathogenic mechanisms apart from the well-documented activation of JAK2/MPL-related pathways, but the lack of experimental models harboring CALR mutations in a JAK2/MPL knockout background has hindered the research on these non-canonical mechanisms. In this study, CRISPR/Cas9 was performed to introduce homozygous patient-like calreticulin mutations in a C. elegans model that naturally lacks JAK2 and MPL orthologs. Whole-genome transcriptomic analysis of these worms was conducted, and some of the genes identified to be associated with processes involved in the pathogenesis of MPNs were further validated by qPCR. Some of the transcriptomic alterations corresponded to typically altered genes and processes in cancer and Ph-negative MPN patients that are known to be triggered by mutant calreticulin without the intervention of JAK2/MPL. However, interestingly, we have also found altered other processes described in these diseases that had not been directly attributed to calreticulin mutations without the intervention of JAK2 or MPL. Thus, these results point to a new experimental model for the study of the JAK2/MPL-independent mechanisms of mutant calreticulin that induce these biological alterations, which could be useful to study unknown non-canonical effects of the mutant protein. The comparison with a calreticulin null strain revealed that the alteration of all of these processes seems to be a consequence of a loss of function of mutant calreticulin in the worm, except for the dysregulation of Hedgehog signaling and flh-3. Further analysis of this model could help to delineate these mechanisms, and the verification of these results in mammalian models may unravel new potential therapeutic targets in MPNs. As far as we know, this is the first time that a C. elegans strain with patient-like mutations is proposed as a potential model for leukemia research.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Guijarro-Hernández

Eder-Azanza

Hurtado

et al. 2023

Cells

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“…IFNα selectively induces cycling of the JAK2V617F HSC, leading to cell cycle stressassociated genomic instability and increased susceptibility towards PARP inhibition, particularly in cells with defective DNA repair mechanisms. To our knowledge, this therapeutic approach of combining PARP inhibitors with IFNα has not been investigated yet and holds potential for application in non-familial MPN patients as well, as BRCA1 is epigenetically inactivated in 40% of all MPN samples analyzed [22], and alterations in DNA repair genes are a frequent feature in MPN patients [27]. This suggests that effective treatment options targeting defective DNA repair mechanisms might extend beyond familial MPN cases to encompass a larger cohort of MPN patients who could benefit from this targeted therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

Bermes,

Rodriguez,

de Toledo

et al. 2023

IJMS

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Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1+/− cells compared to Brca1+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1+/− cells compared to Brca1+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1+/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2V617F MPN driver mutation.

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Clinical potential of ATM inhibitors

Lavin

Yeo

2020

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Transcriptional alteration of DNA repair genes in Philadelphia chromosome negative myeloproliferative neoplasms

Cited by 3 publications

References 27 publications

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model

Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

Clinical potential of ATM inhibitors

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