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Normal and Leukemic Stem Cells Fight for a Place to Call Home

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Review of “Functional Niche Competition between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells” from Stem Cells by Stuart P. Atkinson

The interaction of bone marrow hematopoietic stem and progenitor cells (HSPCs) with their normal residence (or “niche”) is key to the long-term function of the hematopoietic system and detailed knowledge of this interaction has led to improved HSPC transplantation outcomes. However, leukemic stem cells (LSCs) may also interact with this niche [1] with important therapeutic implications for autologous and allogeneic stem cell transplantation.

In a new study, researchers from the group of Cynthia E. Dunbar have explored this concept using the mixed lineage leukemia-AF9 (MLL-AF9) murine model of acute myeloid leukemia (AML) and have shown for the first time that normal HSPCs and LSCs do compete for the same functional niche [2].

The group first used competitive transplantation experiments to show that increasing numbers of whole bone marrow (WBM) cells or purified HSPCs improved survival in a dose-dependent manner in mice also infused with MLL-AF9 myeloid LSCs. The infusion of normal stem cells also reduced leukemia progression as demonstrated by a reduction in leukemic cell localization to the spleen and femurs and mediated a dose-dependent increase in survival.

This effect could be due to healthy stem cells providing some kind of paracrine support to inhibit LSC growth. However, the authors ruled this possibility out by directly assessing LSC competition for the normal hematopoietic niche using confocal microscopy combined with two-photon imaging of the sternal bone marrow following competitive transplantation. This demonstrated distinct foci within the marrow of either green fluorescent protein (GFP)-marked MLL-AF9 cells or dsRed WBM cells, but never a mixture of both. Additionally, as the leukemia progressed, GFP signals replaced dsRed signals (See Figure) suggesting that MLL-AF9 LSCs do compete for the normal HSPC niche, and indeed, seem to have a competitive advantage when healthy stem cells are limiting.

The revelation that the good and the bad of our blood stem cells may fight for the right to call the same place home could have profound meaning for both the treatment of blood cancers and also for HSPC transplantations. This corroborates previous xenograft studies [3] and together they suggest strategies that manipulate niche occupancy, such as pharmacologic or antibody-mediated emptying of niches or enhanced niche protection could be therapeutically beneficial.

Discussion Points

  • What do these findings mean for cancer treatment and stem cell transplants?
  • What are the most effective ways to target niche occupancy?
  • Do other cancer stem cell populations “force” normal stem cells from their tissue specific niches?

References

  1. Lane SW, Scadden DT, and Gilliland DG The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood 2009;114:1150-1157.
  2. Glait-Santar C, Desmond R, Feng X, et al. Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells. Stem Cells 2015;
  3. Boyd AL, Campbell CJ, Hopkins CI, et al. Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs. J Exp Med 2014;211:1925-1935.