Leukemia poses a serious challenge to current therapeutic strategies. This has been attributed to leukemia stem cells (LSCs), which occupy endosteal and sinusoidal niches in the bone marrow similar to those of hematopoietic stem cells (HSCs). The signals from these niches provide a viable setting for the maintenance, survival, and fate specifications of these stem cells. Advancements in genetic engineering and microscopy have enabled us to critically deconstruct and analyze the anatomic and functional characteristics of these niches to reveal a wealth of new knowledge in HSC biology, which is quite ahead of LSC biology. In this paper, we examine the present understanding of the regulatory mechanisms governing HSC niches, with the goals of providing a framework for understanding the mechanisms of LSC regulation and suggesting future strategies for their elimination. 1. Introduction A dysfunctional stem cell microenvironment, or niche, contributes significantly to disease pathology, particularly in cancer [1]. Characterization of the cells that form this niche and the mechanisms by which they regulate stem cell function is imperative for understanding the pathophysiology of diseases that arise in this setting. Stem cells have the unique ability to self-renew, differentiate into multiple lineages, and withstand stress signals to survive and function [2, 3]. In the bone marrow, hematopoietic stem cells (HSCs) are essential for the production of both lymphoid and myeloid cells, which are necessary for the body’s immune integrity, oxygen delivery, blood clotting, waste removal, and a multitude of physiologic processes necessary for survival. For some time, the intracellular regulatory environment of HSCs has been studied in the isolation of its confines in the bone marrow, with little emphasis on the effects this environment might have on these cells’ survival and fate specifications [4]. Testing of the prevailing theory, proposed by Schofield, regarding the underlying indispensable role of the bone marrow structure in engineering hematopoiesis [5] became possible only with the advent and introduction of new in vivo technological tools such as intravital multiphoton microscopy (IVM), which is powerful in optical sectioning of deep tissues and providing real-time visualization of cellular interactions [5, 6]. This has led to a radical revolution in the way stem cells are studied in the bone marrow. IVM studies have shown that hematopoiesis depends not only on the cellular biology of HSCs, but also on the microenvironment where they reside, buttressing the
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