Modulators of histone demethylase JMJD1C selectively target leukemic stem cells

Liu

et al. 2022

Cells

The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte–erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network.

Section: Resultsmentioning

confidence: 99%

“…We previously identified specific JMJD1C inhibitors that can preferentially kill MLL r AML or leukemia stem cells [ 16 , 20 , 21 ]. Here, we also developed a potential agonist of JMJD1C by adding staples, based on an atypical α-helix in the zinc finger domain of JMJD1C.…”

Section: Discussionmentioning

confidence: 99%

JMJD1C Regulates Megakaryopoiesis in In Vitro Models through the Actin Network

Liu

et al. 2022

Cells

“…An increasing number of KDM3C inhibitors are entering pre-clinical investigation. The Hu laboratory performed a virtual screen for potential small molecular modulators targeting the Jumonji domain of KDM3C [ 24 , 27 ]. JDI-16 exhibited killing activities against malignant hematopoietic cells and induced apoptosis and differentiation of MLL rearranged AML cells [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…JDI-16 exhibited killing activities against malignant hematopoietic cells and induced apoptosis and differentiation of MLL rearranged AML cells [ 27 ]. In addition, the KDM3C modulator JDM-7 suppressed colony formation of AML cell lines in semi-solid cell culture by decreasing HOXA9-mediated expression patterns [ 24 ]. Pre-clinical data thus provide efficacy of KDM3C inhibition in mouse models of AML.…”

Section: Resultsmentioning

confidence: 99%

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

2021

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

“…For instance, recently, Jiang and colleagues reported the potent anti-leukemic effects of the highly selective AXL kinase inhibitor SLC-391 on MLL-fusion AML stem and progenitor cells in vitro and in vivo [ 230 ]. Additionally, jumonji domain modulator #7 (JDM-7) binds and inhibits histone lysine demethylase JMJD1C and effectively downregulates LSC self-renewal gene HOXA9 to selectively decrease colony formation of leukemic cells in vitro in MLL-rearranged AML [ 231 ]. Intriguingly, small-molecule inhibitors are also designed to disarm leukemic niche signaling.…”

Section: Potential Therapeutic Strategies To Combat Lscsmentioning

confidence: 99%

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

Zhai

Jiang

2022

Biomedicines

Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.