Abstract
The histone demethylase JMJD1C is overexpressed in patients with myeloproliferative neoplasms (MPNs) and has been implicated in leukemic stem cell function of MLL-AF9 and HOXA9-driven leukemia. In the emerging field of histone demethylase inhibitors, JMJD1C therefore became a potential target. Depletion of Jmjd1c expression significantly reduced cytokine-independent growth in an MPN cell line, indicating a role for JMJD1C in MPN disease maintenance. Here, we investigated a potential role for the demethylase in MPN disease initiation. We introduced a Cre-inducible JAK2V617F mutation into Jmjd1c knockout mice. We show that Jmjd1c is dispensable, both for healthy hematopoiesis as well as for JAK2V617F-driven MPN disease initiation. Jmjd1c knockout mice did not show any significant changes in peripheral blood composition. Likewise, introduction of JAK2V617F into Jmjd1c-/- mice led to a similar MPN phenotype as JAK2V617F in a Jmjd1c wt background. This indicates that there is a difference between the role of JMJD1C in leukemic stem cells and in MPN. In the latter, JMJC domain-containing family members may serve redundant roles, compensating for the loss of individual proteins.
Highlights
The pathophysiology of myeloproliferative neoplasia (MPN) remains incompletely understood, despite the discovery of disease defining mutations such as JAK2V617F and C-terminal alterations of CALR
We have previously shown that the histone 3 mono and dimethyl-specific demethylase JMJD1C is overexpressed in MPN patients [1]
While our previous results indicate a possible role for JMJD1C in the pathophysiology of MPN
Summary
The pathophysiology of myeloproliferative neoplasia (MPN) remains incompletely understood, despite the discovery of disease defining mutations such as JAK2V617F and C-terminal alterations of CALR. It is not clear which effectors or pathways are required for disease initiation or maintenance in addition to aberrant JAK/STAT signaling. A rational search for drug combinations can be informed and accelerated by pre-clinical investigation of potential targets. We have previously shown that the histone 3 mono and dimethyl-specific demethylase JMJD1C is overexpressed in MPN patients [1]. JMJD1C participates in an auto-regulatory loop, as it is both a target of the transcription factor NFE2, overexpressed in the large majority
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