Biology subjects

Martens, J. H. A.

Publications and source records attributed to Martens, J. H. A..

4 recordsLinked to original sources

bioRxiv2023

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability factor in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia

The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs in only half of the KMT2A::MLLT3 cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ adult cells. Silencing of HMX3 in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.

cancer biology↗

bioRxiv2022

Differences in anti-viral immune responses in individuals of Indian and European origin: relevance for the COVID-19 pandemic

During the COVID-19 pandemic, large differences in susceptibility and mortality due to SARS-CoV-2 infection have been reported between populations in Europe and South Asia. While both host and environmental factors (including BCG vaccination) have been proposed to explain this, the potential biological substrate of these differences is unknown. We purified peripheral blood mononuclear cells from individuals living in India and the Netherlands at baseline and 10-12 weeks after BCG vaccination. We compared chromatin accessibility between the two populations at baseline, as well as gene transcription profiles and cytokine production capacities upon viral stimulation with influenza and SARS-CoV-2. The chromatin accessibility of genes important for adaptive immunity was higher in Indians compared to Europeans, while the latter had more accessible chromatin regions in genes of the innate immune system. At the transcriptional level, we observed that Indian volunteers displayed a more tolerant immune response to viral stimulation, in contrast to a more exaggerated response in Europeans. BCG vaccination strengthened the tolerance program in Indians, but not in Europeans. These differences may partly explain the different impact of COVID-19 on the two populations.

immunology↗

bioRxiv2018

CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1

The inv(16) acute myeloid leukemia associated CBF{beta}-MYH11 fusion is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for a unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBF{beta} - MYH11 in primary inv(16) patient blasts, upon expression during hematopoietic differentiation in vitro and upon knockdown in cell lines by multi-omics profiling. Our results reveal that primary inv(16) AML cells share common transcriptomic signatures and epigenetic determiners with megakaryocytes and erythrocytes. Using in vitro differentiation systems, we reveal that CBF{beta}-MYH11 knockdown interferes with normal megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1 binding sites upon fusion protein knockdown, and overexpression of GATA2 partly restores megakaryocyte directed differentiation suppressed by CBF{beta}-MYH11. Together, our findings suggest that in inv(16) leukemia, the CBF{beta}-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors.

cancer biology↗

bioRxiv2018

Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic and functional overview of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of epigenetic and transcriptome dynamics reveals an enforced regulation of differentiation, through cellular functions such as: release of proteases, respiratory burst, cell cycle regulation and apoptosis. We observe an early establishment of the cytotoxic capability, whilst the signaling components that activate antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the epigenetic landscape orchestrate the daily production of large number of neutrophils required for innate host defense and provide a comprehensive overview of the epigenomes of differentiating human neutrophils.\n\nKey pointsO_LIDynamic acetylation enforces human neutrophil progenitor differentiation.\nC_LI\n\nO_LINeutrophils cytotoxic capability is established early at the (pro)myelocyte stage.\nC_LI\n\nO_LICoordinated signaling component expression prevents unwanted toxic effects to the bone marrow niche.\nC_LI

immunology↗