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.

The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture

“…Our view of the architecture of haematopoiesis has important implications to our understanding of the initiation of leukaemia. Whereas HSC are versatile, an insult(s) appears to wire the epigenome of HSC regarding lineage choice to a fixed leukaemia cell fate [ 109 ].…”

“…Nevertheless, the findings from colony assays support the notion of inherent versatility of HPC and perhaps indicate that environmental influences in vivo are important for guiding and/or narrowing the trajectories of HSC. HSC are versatile in the pairwise model, because they can step sideways to adopt alternative, closely related, fates, even after they have “made a lineage choice.” The making of the architecture of leukemia and lymphoma, is very different because the lineage output of the transformed counterparts is restricted to a particular pathway [ 107 , 108 , 109 ]. In contrast to the flexibility of HSC, the transformed counterpart essentially dumps cells down a particular pathway.…”

“…The rationale for this and perhaps the cardinal aspect of cell transformation in cancer is that a genetic insult fixates the epigenome to a lineage. Sanchez-Garcia has proposed that the contribution of oncogenes to leukemia is via epigenetic priming of the cells that initiate leukemia and the initial oncogenic insult(s) is/are then dispensable for tumour progression and maintenance [ 109 ]. In other words, there appears to be an insult-wired block to versatility in the leukemia stem cell.…”

The Good, the Bad and the Tick

“…This hypothesis is based in the following rationality: (i) Theileria spp. (Cheeseman and Weitzman, 2015), A. phagocytophilum (Sinclair et al, 2014) and oncogenic factors (González-Herrero et al, 2018) behave as “epigenators” (Berger et al, 2009; Cheeseman and Weitzman, 2015) because they have the potential to trigger intracellular signaling pathways that lead to changes in chromatin status and gene expression, (ii) transcriptional reprograming and proteome modulation are hallmarks of infection by Theileria spp. (Kinnaird et al, 2013) and A. phagocytophilum (de la Fuente et al, 2005; Lee et al, 2008), and oncogenesis (González-Herrero et al, 2018), (iii) transcriptional reprograming and proteome modulation in Theileria spp.…”

Cell Lineage Choice during Haematopoiesis: In Honour of Professor Antonius Rolink

“…All of the progeny of the resulting clonal leukaemia stem cells (LSCs) then progress towards one leukemic lineage. Vicente-Dueñas, Sánchez-García, and colleagues review the notion of epigenetic stem cell rewiring as a driver of cancer, emphasising that this mechanism represents a common mechanism at work in epithelial tumours [ 8 ]. In the case of leukaemia, rewiring fixes the identity of leukaemia cells at the level of HSCs.…”