title: Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia.
abstract: In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Uy
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Yen-Michael S
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Schmidt
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Fletcher
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Trinkaus
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States. Electronic address: dlink@dom.wustl.edu.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D053264:B-Cell Activating Factor / Q000096:biosynthesis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D000069585:Filgrastim / Q000008:administration & dosage / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D010865:Pilot Projects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D055153:Stem Cell Niche / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D055815:Young Adult
chemical_list: D053264:B-Cell Activating Factor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508605:IL7 protein, human; D015851:Interleukin-7; D009363:Neoplasm Proteins; C505719:TNFSF13B protein, human; D015675:Osteocalcin; D005047:Etoposide; D015080:Mesna; D000069585:Filgrastim; D007069:Ifosfamide
keywords: Acute lymphoblastic leukemia; CXCL12; G-CSF; Lymphoid niche; Mobilization