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

Ernst, Philipp; Schnöder, Tina M.; Huber, Nicolas; Perner, Florian; Jayavelu, Ashok Kumar; Eifert, Theresa; Hsu, Chen-Jen; Tubío-Santamaría, Nuria; Crodel, Carl C.; Ungelenk, Martin; Hübner, Christian A.; Clement, Joachim H.; Hochhaus, Andreas; Heidel, Florian H.

doi:10.1038/s41375-022-01611-3

Cited by 7 publications

(4 citation statements)

References 35 publications

(40 reference statements)

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“…KDM4C has been implicated in various malignancies, acting as an oncoprotein. 47 , 51 Recent reports have identified the roles of KDM4C in maintaining AML LSC, 48 and in the leukemogenesis of AML. 47 We observed that ectopic expression of TWIST1 partially rescued the reduction in colony formation and enhancement in apoptosis of human MLL-AF9 + AML cells caused by KD-M4C knockdown ( Online Supplementary Figure S14A, B ), suggesting that the tumor-promoting activities of KDM4C are partly mediated by TWIST1.…”

Section: Discussionmentioning

confidence: 99%

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia

Wang,

Yin,

You

et al. 2023

haematol

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Leukemia stem cells (LSCs) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSCs of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in an H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSCs, and it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

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Section: Discussionmentioning

confidence: 99%

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia

Wang,

Yin,

You

et al. 2023

haematol

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“…This suggests that ATRX alterations might not be subtype-specific biomarkers. JAK2 plays a major role in growth factor signaling and histone modifications [39,40], while TSC2 is a tumor suppressor that inhibits cell growth by downregulating the mTORC1 pathway [41]. Consequently, when altered, these genes might cause uncontrolled cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Genomic Landscape Comparison of Cardiac versus Extra-Cardiac Angiosarcomas

Gozzellino,

Nannini,

Urbini

et al. 2023

Biomedicines

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Angiosarcomas (ASs) are rare malignant vascular entities that can affect several regions in our body, including the heart. Cardiac ASs comprise 25–40% of cardiac sarcomas and can cause death within months of diagnosis. Thus, our aim was to identify potential differences and/or similarities between cardiac and extra-cardiac ASs to enhance targeted therapies and, consequently, patients’ prognosis. Whole-transcriptome analysis of three cardiac and eleven extra-cardiac non-cutaneous samples was performed to investigate differential gene expression and mutational events between the two groups. The gene signature of cardiac and extra-cardiac non-cutaneous ASs was also compared to that of cutaneous angiosarcomas (n = 9). H/N/K-RAS and TP53 alterations were more recurrent in extra-cardiac ASs, while POTE-gene family overexpression was peculiar to cardiac ASs. Additionally, in vitro functional analyses showed that POTEH upregulation conferred a growth advantage to recipient cells, partly supporting the cardiac AS aggressive phenotype and patients’ scarce survival rate. These features should be considered when investigating alternative treatments.

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“…For example, it has been shown that modulation of these post-translationally modified splicing factors downstream of mutated JAK2 kinase had an impact on clonal persistence and progression [ 31 ]. Similar mechanisms have been explored for epigenetic modifiers such as KDM4C or JMJD2C in JAK2-mutated cells [ 32 , 33 ].…”

Section: Additional Mutationsmentioning

confidence: 99%

Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

et al. 2023

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Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution.

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

Cited by 7 publications

References 35 publications

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia

Twist family BHLH transcription factor 1 is required for the maintenance of leukemia stem cell in MLL-AF9+ acute myeloid leukemia

Genomic Landscape Comparison of Cardiac versus Extra-Cardiac Angiosarcomas

Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

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