Abstract IA01: Mechanisms of formation and progression of preleukemic stem cells

Relapse continues to be the most common cause of death in AML and overall cure rates remain low. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in HSC lead to the formation of precancerous/preleukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in leukemia relapse. While the existence and essentiality of such precancerous 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 MDS and AML. Specifically, we discovered critical roles for several nonclustered homeobox transcription factors in pre-LSC, and identified functionally critical and pharmacologically targetable downstream effectors. We also found that enhancer haplodeficiency and consequent minimal reduction of key transcription factors is 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 pharmacologic approaches to therapeutically interfere with these processes.

In summary, recent studies have started to shed light on preleukemic cell states as the earliest origin of MDS and AML, as well as molecular mechanisms driving their formation and progression, which provides a basis for their specific therapeutic targeting for causative treatment of MDS and AML.

Citation Format: Ulrich Steidl. Mechanisms of formation and progression of preleukemic stem cells [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA01.