Biology subjects

Walfridsson, J.

Publications and source records attributed to Walfridsson, J..

3 recordsLinked to original sources

bioRxiv2022

Identification of GTF2IRD1 as a novel transcription factor essential for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood malignancy characterized by clonal accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Transcription factors are the most frequently mutated and dysregulated genes in AML, and they have critical roles in AML pathogenesis and progression. In this study, we performed large-scale RNA interference screens in MLL-AF9-transformed AML cells and identified GTF2IRD1 as a novel transcription factor essential for the survival of various types of myeloid leukemic cells in vitro and in vivo, but not for primary normal hematopoietic cells. Inhibition of GTF2IRD1 reduced the frequency of primary childhood and adult AML cells, including cell populations enriched for leukemia-initiating cells. In animal models for AML, inhibition of GTF2IRD1 significantly delayed the disease progression. Loss of GTF2IRD1 promoted accumulation of AML cells in the G0 phase of the cell cycle but caused minor effects in apoptosis induction. In line with this, RNA sequencing analysis revealed a significant downregulation of E2F targets as a consequence of genetic inhibition of GTF2IRD1. Taken together, we identified GTF2IRD1 as a transcription factor with a selective importance in AML, and our findings may contribute to the development of improved therapeutic inventions for the disease.

cancer biology↗

bioRxiv2022

FOXO dictates initiation of B cell development and myeloid restriction in common lymphoid progenitors

The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs. SUMMARYCommon lymphoid progenitors co-express the transcription factors FOXO1 and FOXO3. Removing FOXO1 and FOXO3 at this developmental stage results in regained myeloid potential, failed establishment of the early B cell gene regulatory program, and the complete loss of the B cell lineage.

immunology↗

bioRxiv2019

Pax6 and KDM5C co-occupy a subset of developmentally critical genes including Notch signaling regulators in neural progenitors

Pax6 is a key transcription factor in neural development. While generally viewed as a transcriptional activator, mechanisms underlying Pax6 function as a repressor is less well understood. Here we show that Pax6 acts as a direct repressor of transcription associated with a decrease in H3K4me3 levels. Genome wide analysis of the co-occupancy of the H3K4 demethylase KDM5C and Pax6 with H3K4me3-negative regions revealed 177 peaks on 131 genes. Specific analysis of these Pax6/KDM5C/H3K4me3-peaks unveiled a number of genes associated with Notch signaling, including Dll1, Dll4, and Hes1. RNA knockdown of PAX6/KDM5C in human neural progenitors resulted in increased DLL4 gene expression, decreased DLL1 expression, and no significant effect on HES1 mRNA levels, differences that could be due to gene-specific variations in the chromatin landscape. Our findings suggest that PAX6 and KDM5C co-regulate a subset of genes implicated in brain development, including members of the Notch signaling family.

molecular biology↗