title: Neutrophil secondary-granule deficiency as a hallmark of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells.
abstract: Acute promyelocytic leukemia (APL) is a neoplasm with the unique chromosomal translocation t(15;17), which involves the retinoic acid receptor alpha gene. All-trans retinoic acid (ATRA) has been used for APL patients as a potent therapeutic agent to induce differentiation of leukemia cells. Although polymorphonuclear leukocytes (PMNs) appearing in the blood and bone marrow during ATRA treatment often possess Auer rods, indicating their neoplastic origin, other morphological abnormalities of PMNs have not been elucidated. We studied the morphological changes of APL cells during ATRA treatment at the ultrastructural level. Although most aberrant primary granules, including Auer rods, became morphologically normal in response to ATRA therapy and the nuclei showed chromatin condensation and lobulation, resulting in the emergence of PMNs, the lobulated nuclei often had nuclear filamentous connections and/or nuclear blebs, indicating some pathological process. Furthermore, PMNs, particularly early in ATRA treatment, lacked neutrophil secondary granules as did the PMNs appearing in a culture of APL cells incubated with ATRA, findings consistent with previously reported data that acute myeloid leukemia cell lines do not produce secondary granule proteins even after induction of differentiation towards mature neutrophils. The present data indicate that ATRA is incapable of inducing complete morphological maturation of APL cells and that secondary-granule deficiency may be a hallmark of aberrantly differentiated leukemic cells.
authors.affiliation: Clinical Laboratory, National Children's Hospital, Setagayu-ku, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Miyauchi
authors.forename: K
authors.initials: K
authors.lastname: Ohyashiki
authors.forename: Y
authors.initials: Y
authors.lastname: Inatomi
authors.forename: K
authors.initials: K
authors.lastname: Toyama
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000648:ultrastructure; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009195:Peroxidase / Q000032:analysis; D014178:Translocation, Genetic; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014212:Tretinoin; D009195:Peroxidase