**3. Factors involved in hematopoiesis**

Hematopoiesis is a highly coordinated process wherein HSCs differentiate into mature blood cells supported by a physical environment called **niche** (Figure 3). The bone marrow

Hematopoietic Stem Cell in Acute Myeloid Leukemia Development 267

Yet, in intrinsic control, the expression of other transcription factors has been shown to be essential for hematopoietic cell development from the earliest stages, as: SCL (stem cell leukaemia hematopoietic transcription factor); GATA-2; gene products involved in cell cycle

Notch-1–Jagged pathway may serve to integrate extracellular signals with intracellular signalling and cell cycle control. Notch-1 is a surface receptor on hematopoietic stem cell membranes that binds to its ligand, Jagged, on stromal cells. This results in cleavage of the cytoplasmic portion of Notch-1, which can then act as a transcription factor (Gordon, 2005).

Fig. 4. Schematic representation of main bone marrow niche cells: A- hematopoietic stem cells, B- adipocytes, C- mesenchymal stem cells, D- reticular cells, E- osteoclasts, and F-

Leukemia is the consequence of stepwise genetic alterations that confer both proliferative and survival advantage, as well as self-renewal capacity to the malignant cells (Lane et al., 2011). When the HSCs processes of self-renewal and differentiation become deregulated or uncoupled, leukemias can result, characterized by an accumulation of immature blast cells that fail to differentiate into functional cells. Two types of abnormal events can lead to leukemia. First, a normal stem cell acquires several mutations (from different types of genetic events) and, due to epigenetic changes that alter its growth control, the resistance to apoptosis is increased, interfering with the ability of its progeny to differentiate. Second, partially differentiated cells restore gene expression patterns that allow them to reacquire the unique self-renewal properties of stem cells while also interferes with their subsequent

Hanahan & Weinberg (2000) described the rules that govern the transformation of normal cells into a malignant cell. The six main properties that define malignant cells are: selfsufficiency in growth signals; insensitivity to growth inhibitory signals; evasion of

osteoblasts.

**4. Leukemia and leukemic development** 

ability to differentiate (Testa, 2011).

control, such as the cyclin dependent kinase inhibitors (CKIs) p16, p21 and p27**.** 

niche is the most important post-natal microenvironment in which HSCs proliferate, mature and give rise to myeloid and lymphoid progenitors. BM is present in the medullary cavities of all animal bones. Unlike secondary lymphoid organs such as spleen with distinct gross structures including red and white pulp, BM has no clear structural features, except for the endosteum that contains osteoblasts. The endosteum region comes in contact with calcified hard bones and provides a special microenvironment to HSCs, which is necessary for the maintenance of HSC activity (Kondo, 2010).

Within the niche, HSCs are believed to receive support and growth signals originating from several sources, including: fibroblasts, endothelial and reticular cells, adipocytes, osteoblasts and mesenchymal stem cells. The main function of the niche is to integrate local changes in nutrients, oxygen, paracrine and autocrine signals and to change HSCs quiescence, trafficking, and/or expansion in response to signals from the systemic circulation (Broner & Carson, 2009). Although the nature of true MSCs remains misunderstood, CXC chemokine ligand 12 (CXCL12) – expressing CD146 MSCs were recently reported to be self-renewing progenitors that reside on the sinusoidal surfaces and contribute to organization of the sinusoidal wall structure, produce angiopoietin-1 (Ang-1), and are capable of generating osteoblasts that form the endosteal niche (Konopleva & Jordan, 2011).

These CXCL12 reticular cells may serve as a transit pathway for shuttling HSCs between the osteoblastic and vascular niches where essential but different maintenance signals are provided. Cytokines and chemokines produced by bone marrow MSCs concentrate in particular niches secondary to varying local production and through the effects of cytokinebinding glycosaminoglycans. Of these, CXCL12/stromal cell–derived factor-1 alpha positively regulates HSCs homing, while transforming growth factors FMS-like tyrosine kinase 3 (Flt3) ligand and Ang-1 function act as quiescence factors.

CXCL12-CXCR4 signaling is involved in homing of HSCs into BM during ontogeny as well as survival and proliferation of colony-forming progenitor cells. The CXCR4-selective antagonist–induced mobilization of HSCs into the peripheral blood further indicates a role for CXCL12 in retaining HSCs in hematopoietic organs. BM engraftment involves subsequent cell-to-cell interactions through the BMSC-produced complex extracellular matrix. Thus, vascular cell adhesion molecule-1 (VCAM-1) or fibronectin is critical for adhesion to the BM derived MSCs.

In this way, the control of hematopoietic stem cell proliferation kinetics is critically important for the regulation of correct hematopoietic cells production. These control mechanisms could be classified in intrinsic or extrinsic to the stem cells, or a combination of both.

Extrinsic control means that self-renewal and differentiation can be controlled by external factors, such as cell–cell interactions in the hematopoietic microenvironment or cytokines as SCF (stem cell factor) and its receptor c-kit, Flt-3 ligand, TGF-β, TNF- and others. Cytokines regulate a variety of hematopoietic cell functions through the activation of multiple signal transduction pathways. The major pathways relevant to cell proliferation and differentiation are the Janus kinase (Jak)/signal transducers and activators of transcription (STATs), the mitogen-activated protein (MAP) kinase and the phosphatidylinositol (PI) 3-kinase pathways.

niche is the most important post-natal microenvironment in which HSCs proliferate, mature and give rise to myeloid and lymphoid progenitors. BM is present in the medullary cavities of all animal bones. Unlike secondary lymphoid organs such as spleen with distinct gross structures including red and white pulp, BM has no clear structural features, except for the endosteum that contains osteoblasts. The endosteum region comes in contact with calcified hard bones and provides a special microenvironment to HSCs, which is necessary for the

Within the niche, HSCs are believed to receive support and growth signals originating from several sources, including: fibroblasts, endothelial and reticular cells, adipocytes, osteoblasts and mesenchymal stem cells. The main function of the niche is to integrate local changes in nutrients, oxygen, paracrine and autocrine signals and to change HSCs quiescence, trafficking, and/or expansion in response to signals from the systemic circulation (Broner & Carson, 2009). Although the nature of true MSCs remains misunderstood, CXC chemokine ligand 12 (CXCL12) – expressing CD146 MSCs were recently reported to be self-renewing progenitors that reside on the sinusoidal surfaces and contribute to organization of the sinusoidal wall structure, produce angiopoietin-1 (Ang-1), and are capable of generating

These CXCL12 reticular cells may serve as a transit pathway for shuttling HSCs between the osteoblastic and vascular niches where essential but different maintenance signals are provided. Cytokines and chemokines produced by bone marrow MSCs concentrate in particular niches secondary to varying local production and through the effects of cytokinebinding glycosaminoglycans. Of these, CXCL12/stromal cell–derived factor-1 alpha positively regulates HSCs homing, while transforming growth factors FMS-like tyrosine

CXCL12-CXCR4 signaling is involved in homing of HSCs into BM during ontogeny as well as survival and proliferation of colony-forming progenitor cells. The CXCR4-selective antagonist–induced mobilization of HSCs into the peripheral blood further indicates a role for CXCL12 in retaining HSCs in hematopoietic organs. BM engraftment involves subsequent cell-to-cell interactions through the BMSC-produced complex extracellular matrix. Thus, vascular cell adhesion molecule-1 (VCAM-1) or fibronectin is critical for

In this way, the control of hematopoietic stem cell proliferation kinetics is critically important for the regulation of correct hematopoietic cells production. These control mechanisms could be classified in intrinsic or extrinsic to the stem cells, or a combination of

Extrinsic control means that self-renewal and differentiation can be controlled by external factors, such as cell–cell interactions in the hematopoietic microenvironment or cytokines as SCF (stem cell factor) and its receptor c-kit, Flt-3 ligand, TGF-β, TNF- and others. Cytokines regulate a variety of hematopoietic cell functions through the activation of multiple signal transduction pathways. The major pathways relevant to cell proliferation and differentiation are the Janus kinase (Jak)/signal transducers and activators of transcription (STATs), the mitogen-activated protein (MAP) kinase and the

osteoblasts that form the endosteal niche (Konopleva & Jordan, 2011).

kinase 3 (Flt3) ligand and Ang-1 function act as quiescence factors.

maintenance of HSC activity (Kondo, 2010).

adhesion to the BM derived MSCs.

phosphatidylinositol (PI) 3-kinase pathways.

both.

Yet, in intrinsic control, the expression of other transcription factors has been shown to be essential for hematopoietic cell development from the earliest stages, as: SCL (stem cell leukaemia hematopoietic transcription factor); GATA-2; gene products involved in cell cycle control, such as the cyclin dependent kinase inhibitors (CKIs) p16, p21 and p27**.** 

Notch-1–Jagged pathway may serve to integrate extracellular signals with intracellular signalling and cell cycle control. Notch-1 is a surface receptor on hematopoietic stem cell membranes that binds to its ligand, Jagged, on stromal cells. This results in cleavage of the cytoplasmic portion of Notch-1, which can then act as a transcription factor (Gordon, 2005).

Fig. 4. Schematic representation of main bone marrow niche cells: A- hematopoietic stem cells, B- adipocytes, C- mesenchymal stem cells, D- reticular cells, E- osteoclasts, and Fosteoblasts.
