Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia

To test the hypothesis that cell cycle regulatory gene abnormalities are de terminants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group proto col for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), a nd p16(INK4A), Aberrant expression occurred in 33 (85%) patients in the fol lowing frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%, Thirteen patients ( 33%) had abnormalities in 2 or more genes. Outcomes were compared in patien ts with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory chara cteristics. The CR rates for patients with 0 to 1 and multiple abnormalitie s were similar (69% and 54%, respectively). Patients with 0 to 1 abnormalit y had a median survival time of 25 months(n = 26; 95% CI, 13-46 months) ver sus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormal ities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone ma rrows and tested for p16(INK4A) expression by immunocytochemistry, In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A), By contrast, pig expression was present in the CD34+lin- compartment In 95% ( median) of 9 patients whose lymphoblasts expressed p16(INK4A), Therefore, c ell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. T he presence of these abnormalities In the stem compartment suggests that th ey contribute to leukemogenesis. Eradication of the stem cell subset harbor ing these abnormalities may be important to achieve cure, (Blood, 2000;95:2 364-2371) (C) 2000 by The American Society of Hematology.