p53 overexpression in myeloid leukemic disorders is associated with increased apoptosis of hematopoietic marrow cells and ineffective hematopoiesis.
Recent evidence has shown that p53 overexpression in leukemic cells may be a consequence of p53 gene mutation or can occur via posttranslational modification mechanisms. While mutant forms of p53 may stimulate cell proliferation and transformation, wild-type p53 may inhibit DNA synthesis and cause leukemic cells to enter apoptosis. Nine bone marrow biopsies of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with known p53 overexpression were analyzed for evidence of apoptosis of both leukemic blasts and of background hematopoietic cells. This was quantified and compared with that seen in p53- AML and MDS and in normal control marrows. The rate of cell death due to apoptosis was measured by in situ end-labeling of fragmented DNA with the following results: mean values of apoptotic cells/mm2 of BM, p53+ AML and MDS (9 cases), 2.41 +/- 1.7; p53- AML and MDS (10 cases), 0.16 +/- 0.1; control marrows (20 samples), 0.05 +/- 0.0. Our results showed a significant association (P < 0.001) between p53 overexpression and increased apoptosis in all cases studied. The difference was entirely caused by the high rate of cell death observed in the erythroid and myeloid precursor cells of these marrows. These findings suggest that p53+ AML and MDS are a distinct group of marrow disorders characterized by a high rate of intramedullary cell death. This may explain why patients with p53+ leukemic disorders show excessive marrow sensitivity to chemotherapy with prolonged marrow suppression associated with the presence of cytogenetically abnormal blasts that display great drug resistance.
Orazi
A
A
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA.
Kahsai
M
M
John
K
K
Neiman
R S
RS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001853:Bone Marrow / Q000737:chemistry / Q000473:pathology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood* / Q000473:pathology*; D008875:Middle Aged; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D016159:Tumor Suppressor Protein p53