title: Effects of iron depletion on CALM-AF10 leukemias.
abstract: Iron, an essential nutrient for cellular growth and proliferation, enters cells via clathrin-mediated endocytosis. The clathrin assembly lymphoid myeloid (CALM) protein plays an essential role in the cellular import of iron by clathrin-mediated endocytosis. CALM-AF10 leukemias harbor a single copy of the normal CALM gene and therefore may be more sensitive to the growth-inhibitory effect of iron restriction compared with normal hematopoietic cells. We found that CALM heterozygous (CALM(HET)) murine fibroblasts exhibit signs of iron deficiency, with increased surface transferrin receptor levels and reduced growth rates. CALM(HET) hematopoietic cells are more sensitive in vitro to iron chelators than their wild type counterparts. Iron chelation also displayed toxicity toward cultured CALM(HET)CALM-AF10 leukemia cells, and this effect was additive to that of chemotherapy. In mice transplanted with CALM(HET)CALM-AF10 leukemia, we found that dietary iron restriction reduced tumor burden in the spleen. However, dietary iron restriction, used alone or in conjunction with chemotherapy, did not increase survival of mice with CALM(HET)CALM-AF10 leukemia. In summary, although CALM heterozygosity results in iron deficiency and increased sensitivity to iron chelation in vitro, our data in mice do not suggest that iron depletion strategies would be beneficial for the therapy of CALM-AF10 leukemia patients.
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Heath
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Lavau
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wechsler
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D045744:Cell Line, Tumor; D015913:Chelation Therapy; D003131:Combined Modality Therapy; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D019266:Iron, Dietary / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007942:Leukemia, Experimental / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D034041:Monomeric Clathrin Assembly Proteins / Q000172:deficiency / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011828:Radiation Chimera; D013154:Spleen / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden
chemical_list: C114359:AF10-CALM fusion protein, human; D001565:Benzoates; D007502:Iron Chelating Agents; D019266:Iron, Dietary; D034041:Monomeric Clathrin Assembly Proteins; D015514:Oncogene Proteins, Fusion; C573094:PICALM protein, mouse; D014230:Triazoles; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox