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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalExperimental Hematology
DOIs
StateAccepted/In press - 2017

Fingerprint

Stem Cell Niche
Retinoids
Tretinoin
Drug Resistance
Hematologic Neoplasms
Gatekeeping
Stem Cells
Catenins
Neoplastic Stem Cells
Hematopoiesis
Residual Neoplasm
Hematopoietic Stem Cells
Neoplasms
Homeostasis
Bone Marrow
Recurrence
Drug Therapy
Enzymes
Population

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

Retinoic acid, CYP26, and drug resistance in the stem cell niche. / Alonso, Salvador; Jones, Richard J; Ghiaur, Gabriel.

In: Experimental Hematology, 2017.

Research output: Contribution to journalArticle

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