Activation of the transcription factor HIF-1 by HMGN1 in Acute Myeloid Leukaemia

Acute myeloid leukaemia (AML) is a disorder in the hematopoietic stem cells causing an overproduction of myeloid stem cells in the bone marrow. The causes of AML remain poorly understood; however, it has been identified that AML is predominantly driven by particular genetic mutations, with only a small percentage due to other factors. The High Mobility Group N (HMGN) is a family of proteins that bind nucleosomes and modulate transcription by opening the chromatin structure for transcription factors (TFs), such as Hypoxia-Inducible Factors (HIF). HIFs are a family of TFs that were originally identified as being activated in the absence of oxygen (hypoxia). HIF-1 is the best characterised of the HIF family, and its activity has been linked to AML disease progression. HMGN1 overexpression is observed in AML, and its knockout reduces leukaemia progression and improves disease phenotype. Our lab identified by CRISPR/Cas9 genome-wide screening that HIF-1 transcription activity is upregulated by HMGN1. This study aims to determine the mechanism by which HMGN1 regulates HIF-1 transcription activity and to identify the contribution of HIF-1 in the pathogenesis of HMGN1-driven AML. Lentivirally transduced inducible knockdown/ overexpression HMGN1 leukaemia cell lines were generated and validated by Western Blots and RT-qPCR. The effect of HMGN1 on HIF-1 activity was assessed in these cells and in combination with HIF-1 inhibitors, using viability assays and CFU assays. Our results demonstrate that HIF-1 activity is regulated by HMGN1 in a panel of AML cell lines and indicate the contribution of particular driver mutations within this transcription activation axis.