Non-Canonical Regeneration in Acute Myeloid Leukemia

Abstract

Adult acute myeloid leukemia (AML) is a malignancy of the hematopoietic system with a dismal survival rate. Mortality is due to high rates of relapse and is believed to be attributed to surviving leukemic cells that lie dormant during chemotherapy induced remission that have stem cell properties. The molecular characteristics of surviving cells driving related regeneration and relapse processes are poorly understood. Canonically, leukemia stem cells (LSCs) are cited as the cause of relapse, but mechanistic studies remain inconclusive. I have identified a unique cell population using relapse models of AML disease in response to chemotherapy and high-resolution single cell transcriptomics. I have termed these cells, regeneration enriched cells (RECs). RECs are devoid of stem cell capacity and contribute to leukemic regeneration through a previously unknown non-canonical regeneration process, now characterized in vitro and in vivo. Further analyses from additional patient samples and patient derived models allowed division of a subset of RECs, with monocytic characteristics, termed leukemic regeneration monocytes (LRMs). LRMs exist in a modulable metastable equilibrium with their non-pathogenic counterparts, non-regeneration monocytes (NRMs), and provide a potential therapeutic vulnerability against non-canonical regeneration. By flow cytometry (FC), both LRMs and RECs predict patient outcome, treatment response, and relapse. I have optimized a clinically compatible and robust FC assay protocol which provides an approach to use REC and LRM detection as previous unknown biomarkers to aide patient management and treatment decisions of AML patients. Overall, this body of work uncovers and defines the framework of non-canonical leukemic regeneration as an alternative to stem-cell-autonomous regeneration and highlights the importance of incorporating non-canonical regeneration in studying AML biology and within AML patient management.