title: High expression of transforming growth factor-beta long cell cycle times and a unique clustering of S-phase cells in patients with acute promyelocytic leukemia.
abstract: Expression of transforming growth factor-beta (TGF-beta), which inhibits the proliferation of hematopoietic progenitors, was investigated simultaneously with cell cycle characteristics in 63 bone marrow biopsies from 23 cases with acute promyelocytic leukemia (APL). Bromodeoxyuridine (BrdU) was administered to every patient (17 newly diagnosed) for determination of the labeling index (LI) and the durations of S-phase (Ts) and the cell cycle (Tc) of leukemic promyelocytes. APL cases had lower LI both in the bone marrow aspirate (6.1% v 11.4%, P = .008) and biopsy (21.1% v 28.0%, P = .001) and longer Tc (93.6 hours v 56.0 hours, P = .002) when compared with other French-American-British subtypes. TGF-beta expression (detected by a monoclonal anti-TGF-beta 2/beta 3 antibody) was dramatically high, especially in interstitial areas of the biopsies. S-phase cells were found as geographically restricted islands of proliferation (GRIPs) in 20 of 22 cases. Weekly biopsies showed an increment in TGF-beta on day 7 of therapy in 13 of 17 cases, while in vivo differentiation was noted in 9 of 15. We conclude that the presence of high TGF-beta expression may explain the biologic basis for the slowly cycling nature of leukemic promyelocytes in APL as well as the unique clustering of S-phase cells observed in GRIPs.
authors.affiliation: University of Cincinnati, OH.
authors.forename: A
authors.initials: A
authors.lastname: Raza
authors.forename: N
authors.initials: N
authors.lastname: Yousuf
authors.forename: A
authors.initials: A
authors.lastname: Abbas
authors.forename: A
authors.initials: A
authors.lastname: Umerani
authors.forename: A
authors.initials: A
authors.lastname: Mehdi
authors.forename: S A
authors.initials: SA
authors.lastname: Bokhari
authors.forename: Y
authors.initials: Y
authors.lastname: Sheikh
authors.forename: K
authors.initials: K
authors.lastname: Qadir
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.forename: M
authors.initials: M
authors.lastname: Masterson
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016196:S Phase; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use
chemical_list: D004273:DNA, Neoplasm; D016212:Transforming Growth Factor beta; D014212:Tretinoin