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Donor cell leukemia – bone marrow niche-induced disease?

Donor cell derived leukemia (DCL) is a very rare complication in the bone marrow transplantation clinic. As reviewed by Dan Kaufman [1], the incidence of DCL is 0.12%-5% with more than 50 published cases, the majority of which remain anecdotal. So, why do “apparently healthy” donor hematopoietic stem cells (HSC) turn out leukemic after transplantation in a pre-conditioned patient? The mechanisms of leukemogenesis from normal HSC after transplant is a black box. But it made us think about bone marrow niche-induce leukemogenesis as a possible cause.

    – existence of pre-malignant clones (leukemic stem cells) in rare donor grafts – cell autonomous mechanism;
    – accelerated telomere shortening in donor HSC, associated with premature replicative senescence and caused by “toxic marrow environment”;
    – malignant bone marrow niche, modified by radiation, chemotherapy and host leukemic cells before transplant.

I think we also shouldn’t exclude a fusion mechanism, where malignant cell-remnants of host can fuse with donor HSC.

Right now all of these possible mechanisms are speculative, but I believe that the “niche theory”, especially, holds the truth. Even if a few factors together likely contribute to DCL development, we can appreciate the significance of defective bone marrow niche involvement. There is evidence which supports a great role of dysfunctional bone marrow niches in hematopoietic malignancies [2]. A recent report [3] showed that abnormal and dysfunctional mesenchymal progenitors in bone marrow niche can promote leukemogenesis from normal HSC. So, even if DCL is very rare in clinic, studying this phenomenon can provide us a clue about niche-dependent hematological diseases.

Excerpt from the review [1]:

We speculate that DCL is an illustration that leukemia development is not entirely cell autonomous. The important influence of the microenvironment must be considered. Studies of cancer stem cells have never made external factors irrelevant to tumorigenesis, but these aspects are often overlooked.

Clearly distinct cell niches, including the endothelium and vasculature and other cell types, have an impact on tumor cell development. A better understanding of DCL may shift the emphasis from the stem cell toward the external homeostatic influence of the bone marrow microenvironment on the HSC. If the niche becomes dysregulated, the homeostatic balance may be disturbed, leading to changes in hematopoietic developmental pathways.