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      Retinoic acid, CYP26, and drug resistance in the stem cell niche.

      1 , 1 , 2

      Experimental hematology

      Elsevier BV

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          Abstract

          The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche, where they endure chemotherapy, survive as minimal residual disease (MRD), and eventually prevail at relapse. Powerful morphogens, such as retinoids, Wnt/βcatenin, Notch, and Hedgehog, control stem cell fates across tissues, including normal and malignant hematopoiesis. The molecular conversations between these pathways and the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence suggesting that cytochrome P450 (CYP26), the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche, with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.

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          Author and article information

          Journal
          Exp. Hematol.
          Experimental hematology
          Elsevier BV
          1873-2399
          0301-472X
          Oct 2017
          : 54
          Affiliations
          [1 ] Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
          [2 ] Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Electronic address: gghiaur1@jhmi.edu.
          Article
          S0301-472X(17)30660-4 NIHMS904077
          10.1016/j.exphem.2017.07.004
          5603425
          28754309

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