F-103 Targeting aberrant transcription in pre-cancerous stem cells

    loading  Checking for direct PDF access through Ovid

Abstract

Relapse continues to be the most common cause of death in acute myeloid leukemia (AML) and many other cancers. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in tissue-specific stem cells lead to the formation of pre-cancerous/pre-leukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in relapse. While the existence and essentiality of such pre-cancerous cell states has been demonstrated in mice and humans, still very little is known about the molecular mechanisms driving pre-LSC formation and progression. We have recently performed molecular studies of pre-leukemic cell states in mouse genetic models as well as primary cells from patients, and discovered new transcription factors and regulatory mechanisms in pre-LSC in myelodysplastic syndromes (MDS) and AML. We have uncovered critical roles for several transcription factors in pre-LSC, and found that enhancer haplodeficiency and resulting minimal reduction of key transcription factors can be sufficient to induce pre-LSC formation and subsequent progression to MDS and AML. Such models provide novel tools for mechanistic study of pre-LSC and their progression to overt MDS and AML, and for the development and testing of pharmacological approaches to therapeutically interfere with these processes.

In summary, recent studies have started to shed light on pre-cancerous stem cell states as the earliest origin of various malignancies including MDS and AML, as well as molecular mechanisms driving their formation and progression. These advances provide a basis for the specific therapeutic targeting of pre-cancerous stem cells for the causative treatment of MDS and AML and other cancers.

Related Topics

    loading  Loading Related Articles