Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies

Ernst, Philipp; Heidel, Florian H.

doi:10.3390/cancers13040612

Cited by 7 publications

(1 citation statement)

References 162 publications

(202 reference statements)

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“…Most studies have found that TL is shorter in AML patients compared to the general population [ 25 , 26 ]. Shortened TL in AML patients was closely associated with prognosis and survival [ 27 ]. Additionally, some studies have observed that longer TL was linked to an increased risk of developing AML, which aligned with our analysis.…”

Section: Discussionmentioning

confidence: 99%

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

Wang,

Liu,

Liang

et al. 2024

Aging

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Objective: Previous studies have demonstrated that various hematologic diseases (HDs) induce alterations in telomere length (TL). The aim of this study is to investigate whether genetically predicted changes in TL have an impact on the risk of developing HDs. Methods: GWAS data for TL and 11 HDs were extracted from the database. The R software package “TwoSampleMR” was employed to conduct a two-sample Mendelian randomization (MR) analysis, in order to estimate the influence of TL changes on the risk of developing the 11 HDs. Results: We examined the effect of TL changes on the risk of developing the 11 HDs. The IVW results revealed a significant causal association between genetically predicted longer TL and the risk of developing acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MANTLE), and hodgkin lymphoma (HODGKIN). However, there was no significant causal relationship observed between TL changes and the risk of developing chronic myeloid leukemia (CML), diffuse large b-cell lymphoma (DLBCL), marginal zone b-cell lymphoma (MARGINAL), follicular lymphoma (FOLLICULAR), monocytic leukemia (MONOCYTIC), and mature T/NK-cell lymphomas (TNK). Conclusions: The MR analysis revealed a positive association between genetically predicted longer TL and an increased risk of developing ALL, AML, CLL, MANTLE, and HODGKIN. This study further supports the notion that cells with longer TL have greater proliferative and mutational potential, leading to an increased risk of certain HDs.

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Section: Discussionmentioning

confidence: 99%

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

Wang,

Liu,

Liang

et al. 2024

Aging

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Developing transcriptomic signatures as a biomarker of cellular senescence

Mahmud,

Pitcher,

Torbenson

et al. 2024

Ageing Research Reviews

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Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

et al. 2022

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Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.

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Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies

Cited by 7 publications

References 162 publications

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study

Developing transcriptomic signatures as a biomarker of cellular senescence

Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

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