title: Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.
abstract: Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy.
authors.affiliation: Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: v.v.hira@amc.uva.nl.
authors.forename: Vashendriya V V
authors.initials: VVV
authors.lastname: Hira
authors.affiliation: Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Electronic address: c.j.vannoorden@amc.uva.nl.
authors.forename: Cornelis J F
authors.initials: CJF
authors.lastname: Van Noorden
authors.affiliation: Department of Translational Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Leukemia Program, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: carrawh@ccf.org.
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
authors.affiliation: Department of Translational Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: maciejj@ccf.org.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands; Department of Translational Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: r.j.molenaar@amc.uva.nl.
authors.forename: Remco J
authors.initials: RJ
authors.lastname: Molenaar
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D055153:Stem Cell Niche / Q000502:physiology*
keywords: Bone marrow; Hematopoietic stem cell niche; Hijacking; Leukemia; Leukemic stem cells; Therapy resistance