The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” versus Oncogene Addiction

Abstract

Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range (“hypoxic” SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal) within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN-adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long-term maintenance of therapy-resistant minimal residual disease.

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions

“…4D). Consistent with the notion that CEBPB translation is inhibited by BCR-ABL1 activity (25) and that hypoxia inactivates BCR-ABL1 to induce LSC quiescence (14), MIR300 induction by hypoxia was associated with decreased BCR-ABL1 activity, but not expression, ( Fig. 4D) and ectopic C/EBPβ-ER TAM expression rescued primary (pri-miR-300) and mature MIR300 expression in normoxic CD34 + CML-BC cells ( Fig.…”

“…S4A). Thus, MIR300 induction may depend on BM osteogenic niche factors (e.g., MSCs, hypoxia, TGFβ1), known to inhibit growth and induce quiescence of leukemic cells (13,14).…”

“…The mechanisms underlying CML LSC quiescence, survival and self-renewal, and reduced NK-cell number and cytotoxicity likely result from integration of CML cell-autonomous and BMM-generated signals (1,6). The latter are triggered by BM niche-specific metabolic conditions (e.g., oxygen tension), cell-to-cell direct, and soluble and/or exosome-encapsulated factor [e.g., microRNA (miRNA)]-mediated interactions between leukemic, mesenchymal stromal (MSC), endothelial, and immune cells (13)(14)(15).…”

The 14q32.31DLK1-DIO3 MIR300 tumor suppressorpromotes leukemogenesis by inducing cancer stem cell quiescence and inhibiting NK cell anti-cancer immunity

“…Thus, MIR300 induction in CML/AML qLSCs and its ability to increase the quiescent fraction of leukemic but not normal CD34 + cells implies that BM osteogenic niche metabolic and cellular factors (e.g. MSCs, hypoxia), known to inhibit growth and induce quiescence of leukemic cells [12][13][14] , may selectively favor LSC entry into quiescence by increasing MIR300 expression and regulating its anti-proliferative activity in CD34 + LSCs (Fig. 5a right).…”

“…oxygen tension), cell-to-cell direct and, soluble and/or exosome-encapsulated factor (e.g. miRNAs, TGFb1)-mediated interactions between tumor, mesenchymal stromal (MSCs), endothelial (EC) and immune cells 6,[13][14][15] .…”