Loss of a whole chromosome S or a deletion of its long arm (5q) is a recurring abnormality in malignant myeloid neoplasms. To determine the location of genes on Sq that may be involved in leukemogenesis, we examined the deleted chromosome 5 homologs in a series of 135 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. Distal Sq contains a number of genes encoding growth factors, hormone receptors, and proteins involved in signal transduction or transcriptional regulation. These include several genes that are good candidates for a tumorsuppressor gene, as well as the genes encoding five hematopoietic growth factors (CSF2, IL3, IL4, IL5, and IL9). By using fluorescence in situ hybridization, we have refrned the localization of these genes to 5q31.1 and have determined the order of these genes and of other markers within 5q31. By hybridizing probes to metaphase cells with overlapping deletions involving 5q31, we have narrowed the critical region to a smail segment of 5q31 containing the EGRI gene. The five hematopoietic growth factor genes and seven other genes are excluded from this region. The EGRI gene was not deleted in nine other patients with acute myeloid leukemia who did not have abnormalities of chromosome 5. By physical mapping, the minimum size of the critical region was estimated to be 2.8 megabases. This cytogenetic map of 5q31, together with the molecular characterization of the critical region, will facilitate the identification of a putative tumor-suppressor gene in this band.Recurring chromosomal rearrangements are characteristic of human malignant diseases, particularly the leukemias and lymphomas (1) (93%o) had a clonal chromosomal abnormality and 97 (75%) had loss or deletion of chromosome 5 and/or 7. Among these 97 patients, 21 had loss of chromosome 5, 26 had a del(5q), 8 had loss of 5q following unbalanced translocations, 51 had loss of chromosome 7, 11 had a del(7q), and 12 had loss of 7q as a result of an unbalanced translocation. Thirty-one patients had abnormalities of both chromosomes 5 and 7. Overall, 55 patients (43%) had abnormalities of chromosome 5. A del(5q) was the most common structural aberration in our series.In addition to t-MDS/t-AML, a -5/del(Sq) has also been observed in the malignant cells of 10%o ofpatients with AML de novo and in 15% ofpatients who have MDS arising de novo (8). Many of these patients have had significant occupational exposure to potential environmental carcinogens, suggesting that abnormalities of chromosome 5 or 7 may be a marker of mutagen-induced leukemia. A distinct clinical syndrome associated with a del(5q) is seen in a subset ofpatients with MDS de novo. Clinically, this disorder, termed the "5q-syndrome," is characterized by refractory anemia (RA). These patients having a del(Sq) as the sole abnormality tend to have a relatively mild course that usually does not progress to ...

Clinical, histologic, and cytogenetic features in 63 patients with a therapy-related myelodysplastic syndrome (t-MDS) or acute nonlymphocytic leukemia (t-ANLL) following cytotoxic chemotherapy or radiotherapy for a previous disease were analyzed. Eleven patients had received only radiotherapy for the primary disorder. In most cases, high doses had been administered to treatment ports that included the pelvic or spinal bone marrow. Twenty-one patients had received only chemotherapy for their primary disease, all for more than 1 year and all but one with an alkylating agent, either alone or in combination with other drugs. Thirty-one patients had received both radiotherapy and chemotherapy, either concurrently or sequentially. A clonal chromosomal abnormality was observed in marrow or blood cells from 61 of the 63 patients (97%). Fifty-five patients (87%) had a clonal abnormality of chromosomes no. 5 and/or 7 consisting of loss of all or part of the long arm of the chromosome. The critical chromosome region that was consistently deleted in all 17 patients with del(5q) comprised bands q23 to q32. In addition to nos. 5 and 7, five other chromosomes (no. 1, 4, 12, 14, and 18) were found to be nonrandomly involved. Both t-MDS and t-ANLL are late complications of cytotoxic therapies that have distinctive clinical and histologic features and are associated with characteristic aberrations of chromosomes no. 5 and 7. It seems likely that these two chromosomes contain genes involved in the pathogenesis of these hematopoietic neoplasms.

We identified 18 patients with an inversion of chromosome 16, inv(16)(p13q22), among 308 patients with newly diagnosed acute nonlymphocytic leukemia. Each of these 18 patients had acute myelomonocytic leukemia (M4 subtype) and eosinophils with distinctly abnormal morphology, cytochemical staining, and ultrastructure. These eosinophils constituted from 1 to 33 per cent of the nucleated marrow cells. In our series, every patient with acute myelomonocytic leukemia and abnormal eosinophils also had an abnormal chromosome 16. This subgroup of M4 patients had a good response to intensive therapy designed to induce remission; 13 of 17 treated patients entered a complete remission, and 10 remain in first remission. Thus, patients with an inversion of chromosome 16 appear to represent a unique cytogenetic-clinicopathological subtype of acute nonlymphocytic leukemia with a favorable prognosis.

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II- reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

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We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.

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Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.