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Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2364-2371
Cell cycle regulatory gene abnormalities are important
determinants of leukemogenesis and disease biology in adult acute
lymphoblastic leukemia
Wendy Stock,
Tsuong Tsai,
Carla Golden,
Cathy Rankin,
Dorrie Sher,
Marilyn L. Slovak,
Maria G. Pallavicini,
Jerald P. Radich, and
David H. Boldt
From the Department of Medicine, University of Illinois at Chicago,
Chicago, IL; the Department of Medicine, University of Texas Health
Science Center, the Audie L. Murphy Memorial Veterans Hospital, and the
Southwest Oncology Group Leukemia Biology and Cytogenetics Programs,
San Antonio, TX; the Cancer Center, University of California, San
Francisco, CA; the Department of Hematology/Oncology, Children's
Hospital, Oakland, CA; the Southwest Oncology Group Statistical Center
and the Program in Genetics, Clinical Research Division, Fred
Hutchinson Cancer Research Center, Seattle, WA; and the Department of
Cytogenetics, City of Hope National Medical Center, Duarte, CA.
To test the hypothesis that cell cycle regulatory gene abnormalities
are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a
Southwest Oncology Group protocol for abnormalities of the genes,
retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant
expression occurred in 33 (85%) patients in the following frequencies:
Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had
abnormalities in 2 or more genes. Outcomes were compared in patients
with 0 to 1 abnormality versus patients with multiple abnormalities.
The 2 groups did not differ in a large number of clinical and
laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%,
respectively). Patients with 0 to 1 abnormality had a median survival
time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months
(n = 13; 95% CI, 4-12 months) for those with multiple
abnormalities (P < .01). Stem cells (CD34+lin )
were isolated from adult ALL bone marrows 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, p16
expression was present in the CD34+ lin compartment in 95%
(median) of 9 patients whose lymphoblasts expressed p16(INK4A).
Therefore, cell cycle regulatory gene abnormalities are frequently
present in adult ALL lymphoblasts, and they may be important
determinants of disease outcome. The presence of these abnormalities in
the stem compartment suggests that they contribute to leukemogenesis.
Eradication of the stem cell subset harboring these abnormalities may
be important to achieve cure.
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