Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

Abstract

Chronic myeloid leukemia (CML) has been a "model disease" with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.

Keywords: bone marrow microenvironment; chronic myeloid leukemia; combination therapies; history; metabolism; targeted therapy.

Figure 1

(A) Schematic depicting the hierarchy of normal hematopoiesis inside the bone marrow. Hematopoietic stem cells reside at the top of the hierarchy. During differentiation, cells subsequently commit to different lineages ending in their terminal differentiation. The cells of the normal hematopoietic lineage are shown as circles with differentially colored nuclei representing different maturation states or lineages. (B) Diagram illustrating the characteristics, properties and signaling pathways following the transformation of hematopoietic stem cells to chronic myeloid leukemia (CML) stem cells. The smaller circle at the bottom shows the LSC and above is the magnified image of the LSC showing the relevant cell surface receptors, components of the cytoskeleton (elongated black lines—F-actin), cytoplasmic adaptor proteins, mitochondria (yellow), and transcription factors associated with CML stem cells are also shown (in a gray circle representing the nucleus inside the LSC). HSC = hematopoietic stem cell; MPP = multipotent progenitor cell, CLP = common lymphoid progenitor cell; CMP = common myeloid progenitor cell; GMP = granulocyte-macrophage progenitor cell; MEP = megakaryocyte-erythrocyte progenitor cell; LSC = leukemic stem cell; PI3K = phosphoinositide 3-kinase; PRC = polycomb receptor complex; CXCR4 = C-X-C chemokine receptor type 4; STAT5 = signal transducer and activator of transcription 5.

Figure 2

Schematic delineating the anatomy of the bone marrow microenvironment of CML (stem) cells, as well as their interactions with different niche cell types, secreted factors (whose variety is represented by different shapes and colors) and components of the extracellular matrix. Different strategies for targeting these interactions between CML stem cells and their microenvironment in combination therapies are presented in red. The black arrows represent interactions which are known, while the gray arrows represent possible interactions which have not yet been described. EVs = extracellular vesicles; SDF-1 = stromal-derived factor 1 (= C-X-C motif chemokine 12 (CXCL12)); IL = interleukin; ECM = extracellular matrix; sKit = soluble Kit; sICAM = soluble intercellular adhesion molecule; MMP-2/9 = matrix metalloproteinase-2/-9; TGF$\beta$1 = transforming growth factor $\beta$ 1; TGF$\beta$RII = transforming growth factor receptor II; CXCR-4 = C-X-C chemokine receptor type 4.

Figure 3

Strategies for targeting CML stem cells (in red) with tyrosine kinase inhibitors (TKIs) and other agents in combination therapies. TGF$\beta$1 = transforming growth factor $\beta$ 1; EZH2 = Enhancer of zeste homolog 2; BCL-2 = B-cell lymphoma 2; PI3K/AKT = phosphoinositide 3-kinase/AKT Serine/Threonine Kinase 1; IFN$\alpha$ = interferon $\alpha$; MDM2 = MDM2 proto-oncogene; JAK-STAT = Janus kinase (JAK)-signal transducer and activator of transcription.