Leukemic Stem Cells Identities: A Philosophical Analysis

What are leukemic stem cells (LSCs)? This is a biological, a semantic, and a philosophical question. Leukemic stem cells raise a number of questions for onco-hematologists in particular when it comes to their clinical relevance. What are their functions in the initiation and in the progression of the disease? How to identify them? How to target them without damaging the non-malignant hematopoietic stem cells (HSCs)? Given that LSCs come from HSCs or progenitors, a semantic question arises: should we rather call them leukemic initiating cells? or leukemic propagating cells? As a philosopher, I approach all these biological and semantic issues with a slightly different perspective. Instead of asking what are LSCs, I will start by asking what kind of property is stemness.

In previous work, I performed an analysis of the scientific literature on stem cells (including cancer stem cells) and framed a classification of their possible identities (Laplane, HUP 2016; reviewed in Clevers, Nature 2016):

1. Categorical: stemness is a purely intrinsic property (e.g. of categorical property: the atomic number of chemical elements).

2. Dispositional: stemness is an intrinsic property whose expression depends on extrinsic stimuli from the niche (e.g. of dispositional property: fragility).

3. Relational: stemness is an extrinsic property that depends on a relationship between the cell and its environment; the microenvironment can induce stemness (e.g. of relational property: being the sister of someone).

4. Systemic: stemness is an extrinsic property, maintained and controlled at the level of the system (e.g. of systemic properties: soccer positions that depend on the system of play)

Here, I applied this framework to LSCs, in particular in acute myeloid leukemia. This analysis of the identity of stemness matters for onco-hematology because we cannot get rid of categorical, disposition, relational, and systemic properties in the same way. Thus, different therapeutic strategies will have different efficacy depending on the identity of LSCs. For example, targeting LSCs will be much more efficient if they are categorical or dispositional. Targeting the stem cell niche will be more efficient if they are dispositional or relational. But both strategies will lack efficiency if they are systemic. In such cases multi-drug treatments will predictably be more appropriate than targeted therapies.

We think about properties as having fixed identities. This is how we study, learn, teach, and investigate biology, and more generally this is how we think. This typological thinking, inherited from Aristotle and Plato, applies well to normal hematopoiesis where most if not all reports describe stemness as a dispositional property. However, the progression of hematological malignancies, from clonal hematopoiesis and pre-malignant stages to chronic and acute leukemia, questions the relevance of this typological thinking in cancer. A first question is whether HSCs, pre-LSCs, and LSCs have the same identity. A second one is whether LSCs of different hematological malignancies and the LSCs in one patient all have the same identity. I will discuss cases of genetic and epigenetic alterations that suggest possible switches in stemness identity and their consequences for therapies.

To conclude, I used a classical philosophical method developed in three steps: i- analysis of the scientific literature, ii- production of conceptual distinctions, iii- analysis of their consequences. I suggested the distinction between four stemness identities (categorical, dispositional, relational, systemic). HSCs fits the dispositional identity, suggesting that both LSCs-targeting and niche-targeting therapies could be efficient (provided that we can identity and target them properly). However, the identity of LSCs can differ from that of HSCs. Moreover, in contrast with HSCs that have one unique and stable identity, LSCs can be categorical, dispositional, relational, or systemic, and they can switch from one to another identity following particular genetic and epigenetic insults. This drastically complicates the therapeutic approaches and highlights the need to develop multiple therapies.

References

Laplane L, Cancer Stem Cells: Philosophy and Therapies. Harvard University Press, Cambridge (MA), 2016.

Clevers H, Cancer Therapy: Defining Stemness. Nature 2016; 534(7606): 176-177.