Abstract
Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. While complete remission can be obtained with intensive chemotherapy in young and fit patients, relapse is frequent and prognosis remains poor. Leukemic cells are thought to arise from a pool of leukemic stem cells (LSCs) which sit at the top of the hierarchy. Since their discovery, more than 30 years ago, LSCs have been a topic of intense research and their identification paved the way for cancer stem cell research. LSCs are defined by their ability to self-renew, to engraft into recipient mice and to give rise to leukemia. Compared to healthy hematopoietic stem cells (HSCs), LSCs display specific mutations, epigenetic modifications, and a specific metabolic profile. LSCs are usually considered resistant to chemotherapy and are therefore the drivers of relapse. Similar to their HSC counterpart, LSCs reside in a highly specialized microenvironment referred to as the “niche”. Bidirectional interactions between leukemic cells and the microenvironment favor leukemic progression at the expense of healthy hematopoiesis. Within the niche, LSCs are thought to be protected from genotoxic insults. Improvement in our understanding of LSC gene expression profile and phenotype has led to the development of prognosis signatures and the identification of potential therapeutic targets. In this review, we will discuss LSC biology in the context of their specific microenvironment and how a better understanding of LSC niche biology could pave the way for new therapies that target AML.
Highlights
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults
Stem cell gene expression signatures have been shown to have a prognostic impact in AML, highlighting the potential role of leukemia stemness in treatment response [25]
According to the cancer stem cell theory, leukemic stem cells (LSCs) sit at the top of the hierarchy and are the source of the more differentiated leukemic blasts
Summary
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. AML is characterized by the clonal proliferation of abnormal hematopoietic progenitors leading to blood and bone marrow infiltration and hematopoietic failure [1]. Similar to normal hematopoietic stem cells (HSCs), LSCs are able to differentiate and self-renew suggesting a leukemic hierarchy [12,13,14,15,16]. Like their normal counterpart, LSCs reside in the bone marrow in a specialized microenvironment termed “niche”. Studies have suggested a major role of osteoblasts in hematopoiesis by showing hematopoietic stem and progenitor cells (HSPCs) and osteolineage cells in close proximity at steady state and after bone marrow transplantation, osteoblasts have the capacity to support HSPCs in vitro [47,48,49,50]. The exact location of LSCs within the bone marrow niche still needs to be clarified, it is clear that the microenvironment plays a role in leukemogenesis and that leukemic cells can alter the bone marrow at the expense of physiological hematopoiesis
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