The Making of Leukemia

Abstract

Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the developmental history of leukemia. Studies on different types of hematopoietic tumors have shown that the contribution of oncogenes to leukemia is mainly mediated through the epigenetic reprogramming of the leukemia-initiating target cell. This driving of cancer by a malignant epigenetic stem cell rewiring is, however, not exclusive of the hematopoietic system, but rather represents a common tumoral mechanism that is also at work in epithelial tumors. Tumoral epigenetic reprogramming is therefore a new type of interaction between genes and their target cells, in which the action of the oncogene modifies the epigenome to prime leukemia development by establishing a new pathological tumoral cellular identity. This reprogramming may remain latent until it is triggered by either endogenous or environmental stimuli. This new view on the making of leukemia not only reveals a novel function for oncogenes, but also provides evidence for a previously unconsidered model of leukemogenesis, in which the programming of the leukemia cellular identity has already occurred at the level of stem cells, therefore showing a role for oncogenes in the timing of leukemia initiation.

Keywords: cancer therapy; leukemia; leukemia stem cell; mouse model; oncogenes; reprogramming; stem cells.

Figure 1

Oncogene addition versus reprogramming cancer predisposition. (A) In physiological conditions, the survival of a cell is determined by a specific survival pathway that needs to be activated by a vital ligand recognized by a specific receptor. If this vital ligand is removed from the niche/environment, the cell will die. (B) The oncogene addition hypothesis implies that a tumoral cell is able to grow independently of the survival signals because the oncogene activates survival pathways that maintain the tumor cell alive without vital ligands in the niche. The oncogene addition model implies that the inhibition of the oncogene in the tumor cells leads to the tumor cell death, as the survival pathways are no longer active. But under this scenario the evidence from the clinic indicates that only non-CSCs die. (C) The tumor reprogramming model of cancer initiation suggests that tumor stem cells are not oncogene addicted because there is a different function for oncogenes within CSCs. In this model, the target cancer cell of origin is not addicted neither to the oncogenes nor to the environmental signals.

Figure 2

Proposed model for the role of human cancer gene defects in the making of a leukemia. (A) In the development of every normal tissue, a small pool of multipotent stem cells maintains multiple cell lineages. (B) Traditionally, human cancer genetic defects have been thought to act on cells already committed to a differentiation program. Hence, the cancer phenotype closely resembles that of the initial differentiated target cell. (C) Normal uncommitted stem and progenitor cells are the targets for transformation in some human cancers, and the human cancer-gene defects into these cells are the instigators of lineage choice decisions, which are therefore dictated by the oncogene and not by the cell-of-origin phenotype. Consistent with this is the finding that forced expression of these genes in stem cells can select or impose a specific cancer-lineage outcome. This explains why specific gene defects are usually found only in one type of cancer (see text for details). Dotted lines depict cell lineage choices that were not imposed by the oncogene.

Figure 3

Driving of cancer by a malignant epigenetic stem cell rewiring. Different types of mesenchymal (A) and epithelial (B) malignancies have shown that the contribution of oncogenes to cancer development is mainly mediated through the epigenetic reprogramming of the cancer-initiating target cell. As illustrated, specific genotype alterations associated to human cancer (medium circle) give rise to specific phenotypes (outer circle) when targeted to the stem cell/progenitor compartment (see text for details). Chronic Myeloid Leukemia (CML), Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL), precursor B-cell Acute Lymphoblastic Leukemia (pB-ALL), N-butyl-N-4-hydroxybutyl nitrosamine (BBN).

Figure 4

Schematic representation of the emergence of LSCs in the making of a leukemia. A mutation occurs in HSCs leading to the emergence of aberrant pre-leukemic HSCs. These aberrant pre-leukemic HSCs self-renew and expand within the HSC compartment. Pre-leukemic HSCs give rise to a high number of lineage-committed progenitors harboring this identical mutation. This leads to an increased chance of acquiring the additional oncogenic/environmental events, which finally transform the aberrant progenitor cells from pre-leukemic HSCs into the leukemic stem cells (LSCs). Loss of differentiation potentials is essential for the emergence of LSCs. LSCs are reprogrammed by an oncogenic insult to an invariant cell lineage. Hematopoietic stem cell (HSC), Multipotent progenitor cell (MPP), Lymphoid-primed MPP compartment (LMPP), Common myeloid progenitor (CMP), Common lymphoid progenitor (CLP), Early progenitor with lymphoid and myeloid potential (EPLM), Granulocyte-macrophage progenitor (GMP), Monocytes (Mon), Eosinophil-granulocyte-macrophage (EoGM), Granulocyte-macrophage progenitor-colony forming unit (GM-CFU), Dendritic cell (DC), Megakaryocyte-erythroid progenitor (MEP), Natural Killer cell (NK), Eosinophil/Basophil-colony forming unit (Eo/B-CFU).

Figure 5

Epigenetic reprogramming and cancer therapy. (A) Epigenetic reprogramming can be the mechanism used by tumors to evade CD19 CAR immune therapy. (B) Epigenetic reprogramming can be exploited in therapy to kill leukemia/cancer stem cells. Recent findings indicate that rewiring the epigenetic programming of tumor cells is a viable prospect (see text for details).