The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults.
Chromosomal translocations are commonly found in de novo acute myeloid leukemia (AML) cells, and the fusion proteins produced from these genetic abnormalities are assumed to contribute directly to leukemogenesis and/or progression. The AML1/ETO fusion protein, created by translocations between chromosomes 8 and 21 [t(8;21); G. Nucifora and J. D. Rowley, Leuk. Lymphoma, 14: 353-362, 1994; K. L. Rhoades et al., Proc. Natl. Acad. Sci. USA, 93: 11895-11900, 1996] can induce anti-apoptotic Bcl-2 expression in vitro and was proposed to thereby promote the survival of t(8;21)-bearing AML cells (L. Klampfer et al., Proc. Natl. Acad. Sci. USA, 93: 14059-14064, 1996). We confirm that cells of the t(8;21)-bearing Kasumi cell line do express high levels of Bcl-2 protein, as reported previously. However, we show that primary AML cells with (8;21) chromosomal translocations generally express low levels of Bcl-2 protein relative to normal bone marrow-derived myeloid cells and to AML samples with other simple karyotypic abnormalities. We note that p53 mutations are present in the myeloid cell lines expressing AML-ETO protein from chromosomal translocations (Kasumi and SKNO) or from transfected fusion genes (U937) but were undetected in our analyses of 28 primary t(8;21)-bearing AML cell samples from de novo AMLs. Because wild-type p53 can transcriptionally down-regulate bcl-2, we speculate that p53 mutations may contribute to the association of t(8;21) chromosomal abnormalities with higher Bcl-2 expression levels in leukemia cell lines. We also note that some t(8;21)-bearing samples from pediatric and older adult patients do express somewhat higher levels of Bcl-2 than t(8;21)-bearing samples from young adult patients. This suggests that Bcl-2 overexpression could occur in these AML cells by an as yet undefined, p53-independent mechanism and could contribute to the reported association of t(8;21) karyotypes with poor clinical outcomes in childhood AML patients and/or to typically poor clinical outcomes in elderly AML patients.
Banker
D E
DE
Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Radich
J
J
Becker
A
A
Kerkof
K
K
Norwood
T
T
Willman
C
C
Appelbaum
F R
FR
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007118:Immunoassay; D007951:Leukemia, Myeloid / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D015203:Reproducibility of Results; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53