JAK-STAT in Early Hematopoiesis and Leukemia

Abstract

Hematopoietic stem cells (HSCs) produce all the terminally differentiated blood cells and are controlled by extracellular signals from the microenvironment, the bone marrow (BM) niche, as well as intrinsic cell signals. Intrinsic signals include the tightly controlled action of signaling pathways, as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Activation of JAK-STAT leads to phosphorylation of members of the STAT family to regulate proliferation, survival, and self-renewal of HSCs. Mutations in components of the JAK-STAT pathway are linked with defects in HSCs and hematologic malignancies. Accumulating mutations in HSCs and aging contribute to leukemia transformation. Here an overview of hematopoiesis, and the role of the JAK-STAT pathway in HSCs and in the promotion of leukemic transformation is presented. Therapeutic targeting of JAK-STAT and clinical implications of the existing research findings are also discussed.

Keywords: JAK-STAT; STAT5; STATs; hematopoiesis; hematopoietic stem cells; leukemia.

FIGURE 1

Illustration of bone marrow niche, normal and leukemic hematopoiesis. (A) Schematic representation of the bone marrow (BM) niche summarizing key cell types and functional features. HSCs reside in the proximity of BM vessels (arterioles or sinusoids). Mesenchymal stem cell (MSC) populations include, among others, NG2 +, LEPR + and CAR cells and promote HSCs maintenance by releasing important factors (i.e., CXCL12, SCF). Endothelial cells (ECs) (arteriolar endothelial cells (AECs), surrounding the arterioles and sinusoidal endothelial cells (SECs), surrounding the sinusoids) also release important factors for HCSs maintenance. Sympathetic nerve fibers regulate HSCs migration through the sinusoids. MSC subpopulations, ECs, non-myelinating Schwann cells (NMSCs) and HSC progeny (i.e., megakaryocytes) contribute to the regulation of HSC homeostasis or regenerative hematopoiesis. Megakaryocytes produce CXCL4 to regulate HSCs. (B) Schematic representation of normal hematopoiesis. HSCs reside at the top of the hierarchy. Differentiation is considered today more of a continuum, than a step-by-step procedure, represented by the dashed arrow on the left. The HSC pool is heterogeneous in terms of self-renewal and differentiation properties. Self-renewal of HSCs is denoted by an arrow around the cells (solid arrow represents strong and dashed arrow weaker self-renewal potential). Hematopoietic Stem and Progenitor cells (HSPCs) pool contains long-term self-renewing HSCs (LT-HSCs), short-term self-renewing HSCs (ST-HSCs) and non-self-renewing multipotent progenitors (MPPs). Throughout differentiation, HSCs might first lose self-renewal capacity and then lineage potential as they commit to evolving to a mature functional cell of a specific lineage. MPPs, might have unilineage, bi- or trilineage potential. MPPs advance to oligopotent progenitors (OPPs), including the lymphoid-primed multipotent progenitors (LMPPs), the common lymphoid progenitors (CLPs) and the common myeloid progenitors (CMPs). The myeloid and lymphoid compartments remain associated in the hierarchy via the lymphoid-primed multipotent progenitors (LMPP). CMPs give rise to megakaryocyte/erythrocyte progenitors (MEPs) and granulocyte/macrophage progenitors (GMPs). LMPPs give rise to give GMPs and CLPs. The OPPs through the lineage-restricted progenitors give rise to the mature effector cells (B-cells, T-cells and NK-cells, dendritic cells, granulocytes, macrophages, platelets, and erythrocytes). (C) Schematic representation of leukemic hematopoiesis. Aging, mutations, disease, inflammation, niche dysfunction/alterations and clonal hematopoiesis can lead to the generation of a leukemic stem cell (LSC). LSC can differentiate into the hematopoietic lineage carrying the mutation/s or remain as immature progenitor cells, called blast cells. Not all intermediate cell stages are depicted and cells are not in scale. Main differentiation points where the JAK-STAT pathway, JAKs and STATs exert their roles are shown.

FIGURE 2

Connections of JAK-STAT, HSCs and leukemia. Schematic representation of the connections of HSCs-bone marrow niche, JAK-STAT pathway and leukemia is shown. JAK-STAT pathway regulates HSCs proliferation, survival and self-renewal, and components of the BM microenvironment. Mutations linked to JAK-STAT and/or HSCs-niche can lead to leukemic transformation. Research findings on these connections provide opportunities (in the middle of the triangle) for the management and therapy of leukemia. Double arrows represent bidirectional connections. For example mutations in JAK-STAT can cause leukemia, but also in leukemia cells deregulated JAK-STAT pathway is observed. HSC: Hematopoietic stem cell, HSCT: Hematopoietic stem cell transplantation.