No abstract

The loss of bands p21-22 from one chromosome 9 homologue as a consequence of a deletion of the short arm [del(9p)], unbalanced translocation, or monosomy 9 is frequently observed in the malignant cells of patients with lymphoid neoplasias, including acute lymphoblastic leukemia and non-Hodgkin lymphoma. The a-and J31-interferon genes have been assigned to this chromosome region (9p21-22). We now present evidence of the homozygous deletion of the interferon genes in neoplastic hematopoietic cell lines and primary leukemia cells in the presence or absence of chromosomal deletions that are detectable at the level of the light microscope. In these cell lines, the deletion of the interferon genes is accompanied by a deficiency of 5'-methylthioadenosine phosphorylase (EC 2.4.2.28), an enzyme of purine metabolism.

EVI1, located at chromosome band 3q26, encodes a 1051 amino DNA-binding zinc fingers in the central part of the molecule.acid zinc finger protein inappropriately expressed in the leu-EVI1 also contains an acidic domain at the carboxyl terkemic cells of 2-5% of acute myeloid leukemia (AML) and myeminus. 4 The first group of zinc fingers recognizes and binds As expressed in some tissues, and it is activated inappropriately a reporter gene, we used chloramphenicol acetyl transferase by chromosomal rearrangements involving band 3q26 in (CAT) linked to a human normal genomic promoter and to a about 2-5% of human myeloid leukemia with an abnormal synthetic promoter both of which have been previously karyotype.2,3 Expression of EVI1 in hematopoietic cells is condescribed. 11 Our results show that MDS1/EVI1 can activate troversial, but it has been reported for CD34+ cells. 4 The most the promoters almost as strongly as GATA-1. Activation of the frequent rearrangements affecting EVI1 expression are promoters depends strictly on the segment of the PR domain t(3;3)(q21;q26) and inv(3)(q21q26), in which activation of encoded by the second and third untranslated exons of EVI1 EVI1 is due to juxtaposition of the gene to the enhancer region and on the first group of seven zinc fingers. Furthermore, actiof the ribophorin gene. 5 The gene can also be activated folvation by MDS1/EVI1 is repressed by expression of EVI1. To lowing the t(3;21)(q26;q22) in which EVI1 is fused downexamine the relative amounts of the two genes in the bone stream of the runt homology domain of the AML1 gene. 6,7 In marrow, we have analyzed bone marrow samples of a normal addition, the gene can also be activated in cells with an apparindividual and of seven patients with the t(3;3) or the inv(3). ently normal karyotype by unknown mechanisms.8 EVI1 is a Our results indicate that in some of the patients the rearrangenuclear protein containing a group of seven DNA-binding ments affect the expression of EVI1 but not MDS1/EVI1. These zinc fingers at the amino terminus and a second group of three results combined are especially important in view of the fact that recurring chromosomal translocations in leukemia with abnormalities at chromosome band 3q26 often disrupt the Correspondence: G Nucifora, Oncology Institute, Loyola University region between MDS1 and EVI1 and result in truncation

A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.