title: Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function.
abstract: More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Weihuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Grant
authors.initials: G
authors.lastname: Zimmerman
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Jay
authors.initials: J
authors.lastname: Myers
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Stephen
authors.initials: S
authors.lastname: Moreton
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Joseph
authors.initials: J
authors.lastname: Nthale
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Amad
authors.initials: A
authors.lastname: Awadallah
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Rose
authors.initials: R
authors.lastname: Beck
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: David
authors.initials: D
authors.lastname: Wald
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio. lan.zhou@case.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology*; D055815:Young Adult
chemical_list: D051880:Receptors, Notch