The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26. The gene is aberrantly expressed in acute myeloid leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1 (MDS1-EVI1), a gene located 5 of EVI1.

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: 1) Cytogenetics showed a normal 46,XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient 1) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5' BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region.(ABSTRACT TRUNCATED AT 250 WORDS)

Three X/autosomal translocations, two familial and one de novo, were analyzed. Late-replicating chromosomes and chromosome regions were studied with R-banding techniques after BrdU incorporation. The first translocation, t(X;4)(q21;ql3), was a de novo translocation, found in a woman with amenorrhea. The structurally normal X was late replicating in all cells. The second translocation, t(X;6)(p21;q26), was found in an unbalanced form, 46, XX, der(6), in a phenotypically abnormal girl; her mother carried the balanced translocation. In the mother’s blood culture inactivation of the X’s followed two modes: In 85 % of the cells the normal X was late replicating, and in the remaining 15 % the der(X) was inactivated, including the attached fragment of chromosome 6. The third translocation, t(X;17)(pll;q24), was found in three generations. In the phenotypically normal mother, who carried the balanced translocation, the late-replicating X was always the normal X. In her daughters, who had an unbalanced karyotype, 46, X, der(X), and multiple congenital abnormalities, the X part of the translocation chromosome was always late replicating. No spreading of inactivation over the attached autosomal region was observed, resulting for these patients in a partial trisomy of 17q. Their peculiar phenotype is described.

Our retrospective karyotype review revealed two rare recurrent translocations affecting ETV6 (TEL): t(7;12)(q36;p13) and t(7;12)(q32;p13). Five patients with a t(7;12) were from a group of 125 successfully karyotyped pediatric patients enrolled in consecutive clinical AML trials of the Dutch Childhood Leukemia Study Group over a period of 7 years. During a search of available cytogenetic databases, we found 7q and 12p abnormalities in two additional Dutch patients and in three participants in Pediatric Oncology Group trials. A del(12p) had been initially identified in four of these patients and re-examination of the original karyograms revealed a t(7;12)(q36;p13) in two instances and a probable t(7;12) in the other two. FISH confirmed the presence of a t(7;12)(q36;p13) in the latter. Most (n = 7) also had trisomy 19. The t(7;12)(q36;p13) (n = 9) was more common than the t(7;12)(q32;p13) (n = 1). These subtle translocations were found only in children 18 months of age or younger. A literature search revealed that the t(7;12) with breakpoints at 7q31-q36 and 12p12-p13 had been reported in six children with myeloid disorders and in two with acute lymphoblastic leukemia; all were 12 months of age or younger. Only two of the 17 for whom survival data were available, were alive after at least 22 months of continuous complete remission. Our findings suggest that ETV6 rearrangements due to a t(7;12) may play an adverse role in myeloid disorders in children 18 months of age or younger. Therefore, children in this age group with myeloid disorders should be screened for both MLL and ETV6 rearrangements. Leukemia (2001) 15, 915-920.

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