Wnt signaling in normal and malignant hematopoiesis

Abstract

One of the most remarkable characteristics of stem cells is their ability to perpetuate themselves through self-renewal while concomitantly generating differentiated cells. In the hematopoietic system, stem cells balance these mechanisms to maintain steady-state hematopoiesis for the lifetime of the organism, and to effectively regenerate the system following injury. Defects in the proper control of self-renewal and differentiation can be potentially devastating and contribute to the development of malignancies. In this review, we trace the emerging role of Wnt signaling as a critical regulator of distinct aspects of self-renewal and differentiation, its contribution to the maintenance of homeostasis and regeneration, and how the pathway can be hijacked to promote leukemia development. A better understanding of these processes could pave the way to enhancing recovery after injury and to developing better therapeutic approaches for hematologic malignancies.

Figure 1.

Murine embryonic hematopoiesis occurs simultaneously in several organs during development. The mouse embryo generates de novo hematopoietic stem cells (HSCs) in the placenta, yolk sac, and aorta–gonad–mesonephros (AGM) beginning at E7.5. These HSCs then migrate into and seed various organs at the start of definitive hematopoiesis around E11. Normal adult hematopoiesis only occurs in the bone marrow. (Figure created from data in Medvinsky et al. 2011.)

Figure 2.

The hematopoietic stem cell hierarchy in adult bone marrow. All differentiated blood cells are generated from a small pool of self-renewing long-term hematopoietic stem cells (LT-HSCs) (dark green area). LT-HSCs are capable of both self-renewal and differentiation. When LT-HSCs differentiate, they create short-term HSCs (ST-HSCs) with limited self-renewal potential (light green area). The ST-HSCs produce progenitors that give rise to multipotent non-self-renewing common myeloid progenitors (CMP) and common lymphoid progenitors (CLP). These progenitor populations generate mature hematopoietic cells such as macrophages, B and T cells, and red blood cells (erythrocytes). The dashed lines indicate partial lineage connections.