Original Article
Deletions of Interferon Genes in Acute Lymphoblastic Leukemia
N Engl J Med 1990; 322:77-82January 11, 1990
- Abstract
- Abstract
Structural rearrangements involving the short arm of chromosome 9, including bands 9p21 and 22, are found in the leukemia cells of 7 to 13 percent of patients with acute lymphoblastic leukemia. The interferon-α gene cluster and the interferon-β1 gene have been localized to this chromosomal region. We have previously demonstrated deletions of these genes in several cell lines established in vitro from patients with lymphoblastic leukemia.
We report here homozygous or hemizygous deletions of the interferon-α and interferon-β1 genes in samples of leukemia cells from patients with lymphoblastic leukemia. Of 62 patients examined, 18 (29 percent) had such deletions. Four patients (7 percent) had homozygous deletions of the interferon-α gene cluster; of these, one also had a homozygous deletion and three had hemizygous deletions of the interferon-β1 gene. Fourteen patients (23 percent) had hemizygous deletions of both the interferon-α gene cluster and the interferon-β1 gene. In 8 of the 18 patients with deletions, the deletions of interferon genes were submicroscopic; in the 11 other patients, chromosomal rearrangements of 9p, including translocations or deletions, were visible on light microscopy.
These chromosomal and molecular deletions are likely to be related to the loss of a tumor-suppressor gene (or genes) located on 9p, which may be an interferon gene or an unrelated but closely linked gene. (N Engl J Med 1990; 322:77–82.)
Media in This Article
Figure 1
Southern Blots of DNA from Leukemia Cells of Patients with ALL.Figure 2
Dot Blots of DNA from BV173, a Cell Line with a Normal Complement of Interferon Genes, and from Leukemia Cells of Two Patients with a Hemizygous Deletion of the Interferon-α and the lnterferon-β1 Genes.Article Activity
- Article
SPECIFIC chromosomal abnormalities associated with neoplastic diseases appear to be involved in the oncogenic process as a result of either the modification of normal cellular genes that creates dominant oncogenes or the loss of dominant tumor-suppressor genes. Among patients with acute lymphoblastic leukemia (ALL), deletions or unbalanced translocations of the short arm of chromosome 9 have been reported with frequencies of 7 to 13 percent.1 2 3 4 The smallest segment that is lost in each patient includes band 9p22. This region of chromosome 9 contains the cluster of interferon-α genes and the interferon-β1 gene.5
We previously reported the homozygous or hemizygous deletion of the interferon-gene cluster in vitro in 7 of 15 cell lines (47 percent) derived from patients with ALL.6 Four of these gene deletions were associated with visible cytogenetic deletions or other rearrangements of 9p; in three other cases, however, the deletions were submicroscopic. These results demonstrate that genetic lesions of this region of 9p occur with a higher prevalence in cell lines of ALL than is indicated by the frequency of detectable cytogenetic abnormalities of 9p.
To determine whether interferon-gene deletions are associated with the process, of leukemia in vivo, we have analyzed primary leukemia-cell samples from 62 patients with ALL; we now report that deletions of the interferon genes occur frequently among patients with this malignant disease.
Methods
Patients
We studied 62 patients admitted to several Chicago hospitals for the diagnosis and treatment of ALL between 1982 and 1988. Patients were selected for study if samples of bone marrow or peripheral blood collected at diagnosis that contained more than 60 percent blast cells were available for cytogenetic and DNA analysis. A peripheral-blood sample obtained during a first remission was also analyzed (Patient 1). Clinical data were collected retrospectively by reviewing medical records. We also present information about a patient whom we studied previously (Patient 19).6
Cytogenetic Analysis
Cytogenetic analysis was performed with a trypsin—Giemsa banding technique on fresh samples of bone marrow or peripheral blood obtained at the time of diagnosis. We examined metaphase cells from short-term (24- and 48-hour) unstimulated cultures. Chromosomal abnormalities were described according to the International System for Human Cytogenetic Nomenclature.7
DNA Probes
The probes used were a cDNA clone of the human interferonβl gene, a cDNA clone of the human interferon-α2 gene6 that cross-hybridizes to all the genes of the interferon-α1 gene family, and a partial cDNA clone of the transferrin-receptor gene, which served as a control; the transferrin-receptor gene is located on human chromosome 3. The human DNA inserts were separated from the vector sequences by restriction-endonuclease digestion and labeled with [32P]deoxycytidine triphosphate as described previously.6
DNA Analysis
Cells were stored in 10 percent dimethylsulfoxide and frozen at —70°C or in liquid nitrogen before DNA extraction and analysis by Southern blot hybridization. Complete deletion or hemizygosity of the interferon genes was determined by visual inspection of the autoradiographs after sequential hybridization of the same blot to the interferon-α, interferon-β1, and control probes. For an objective evaluation of gene dosage, all samples classified as having hemizygous or homozygous deletions on Southern blotting and some samples without deletions were further analyzed by dot—blot hybridization and densitometry of the autoradiographs. DNA preparation, Southern blot transfer, dot blotting, hybridization, and autoradiography were performed as previously described.6
Results
Characteristics of the Study Population
Of the 62 patients studied, 36 (58 percent) were male and 26 (42 percent) were female. The median age was 14 years; 44 (71 percent) were less than 18 years old. Fifty-seven patients (92 percent) had clonal chromosomal abnormalities in their leukemia cells, and 5 (8 percent) had normal karyotypes. Forty-four patients (71 percent) had at least one recognized recurring abnormality associated with ALL: 7 patients had a hyperdiploid karyotype with more than 50 chromosomes; 7 patients had a t(9;22) (q34;qll); 5 patients had a t(4;11)(q21;q23); 6 patients had a deletion of 6q (one of these patients also had a t(4;ll); 2 patients had a der(19)t(l;19) (q23;pl3); 4 patients had translocations involving 14q32; and 11 patients had a deletion or unbalanced translocation involving 9p (one of these patients also had a t(9;22)). Four patients had other recurring abnormalities, and 13 patients (21 percent) had nonrecurring abnormalities.
Analysis of the Interferon Genes
Deletions of interferon-α genes, the interferon-β1 gene, or both were observed in 18 of the 62 patients with ALL (29 percent). The cytogenetic features and the dosage of the interferon genes of these patients are summarized in Table 1Table 1
Cytogenetic Features of Patients with ALL and Deletions of the Interferon Genes.. Homozygous deletions of interferon genes were found in the leukemia cells of 4 (7 percent) (Patients 1 through 4) (Fig. 1Figure 1Southern Blots of DNA from Leukemia Cells of Patients with ALL.); 14 (23 percent) had hemizygous deletions in their leukemia cells (Patients 5 through 18) (Fig. 2Figure 2Dot Blots of DNA from BV173, a Cell Line with a Normal Complement of Interferon Genes, and from Leukemia Cells of Two Patients with a Hemizygous Deletion of the Interferon-α and the lnterferon-β1 Genes.). Two of the homozygous deletions involved only the interferon-α genes; in both cases, the interferon-β1 gene was hemizygous (Patients 2 and 3) (Fig. 1). In a third patient (Patient 1), both the interferon-α and the interferon-βl genes were completely deleted (Fig. 1). A fourth patient (Patient 4) was found to have a deletion of most of the interferon-α genes in his leukemia cells; the interferonβ1 gene and two interferon-α genes were hemizygous (Fig. 1). Previously, we had observed the complete deletion of interferon-α and interferon-β1 genes in the leukemia cells of a patient with ALL (Patient 19) and in the cell line SUP-T3, which was derived from this patient.6 Patient 1 had a homozygous submicroscopic deletion of interferon-α and interferon-β1 genes in his leukemic cells. The analysis of a peripheral-blood sample obtained at the time of complete remission revealed a normal dosage of the interferon-α and the interferonβl genes in these nonmalignant cells (Fig. 1).
Cytogenetic Features of Patients with Interferon-Gene Deletions
Two of the patients who had homozygous deletions (Patients 1 and 3) and six of those who had hemizygous deletions of the interferon genes (Patients 6, 7, 10, 14, 15, and 18) had no visible loss of material from 9p on light microscopy (8 of 18, or 44 percent) (Table 1). Patients 1 and 10 had balanced translocations involving 9p22 and 9p 13–21, respectively. Two patients who had homozygous deletions (Patients 2 and 4) had a visible deletion of 9p in only one chromosome 9 homologue; they therefore must have had a submicroscopic deletion of the p arm of the other chromosome 9 homologue (2 of 18, or 11.1 percent). Eight patients who had hemizygous deletions (Patients 5, 8, 9, 11, 12, 13, 16, and 17) had a visible deletion or loss of only one 9p arm (8 of 18, or 44 percent). Thus, submicroscopic deletions that include the interferon genes are as frequent as cytogenetically detectable deletions of 9p that include these genes. Other recurring chromosomal abnormalities associated with ALL that did not involve 9p were observed in 5 patients with interferongene deletions (5 of 18, or 28 percent; Patients 6 through 8, 11, and 17).
Cytogenetic abnormalities involving 9p are not invariably associated with deletion of the interferon genes. Three patients with ALL had a rearrangement of 9p, without deletions of the interferon genes. These rearrangements were a t(9; 11 ) (p21;q25), which difiered from the recurring t(9;l I)(p22;q23), a t(9;?) (p24;?), and a del(9)(pl3p22). In the last case, the break in 9p22 must be proximal to the interferon-gene cluster.
Clinical Features and Outcomes in Patients with InterferonGene Deletions
The clinical features and outcome in the 18 patients with interferon-gene deletions and in 1 patient previously described are shown in Table 2Table 2
Clinical Features at Diagnosis and Outcome in Patients with ALL and Deletions of Interferon Genes.*. We did not compare these patients with the patients without interferon-gene deletion because the patients in this retrospective series were not consecutive and were selected according to the availability of frozen cells for study.The 18 patients ranged in age from 1 month to 63 years (median, 10 years); 13 patients (72 percent) were less than 18 years old. There were 12 male (67 percent) and 6 female patients (33 percent). Thus, their age and sex distributions were not different from those of the total study population. No unusual pattern of organ involvement at diagnosis was observed. Lymphadenopathy, splenomegaly, the presence of a mediastinal mass, and central nervous system involvement were found in 6 (33 percent), 12 (67 percent), 4 (22 percent), and 3 (17 percent) patients, respectively. High white-cell counts (range, 3.7 to 982.0×109 per liter; median, 46.9×109) were common among the 18 patients with interferon-gene deletions, but this was a characteristic of our study population (range, 2.1 to 982.0×109 per liter; median, 46.5×109). The morphologic features and the immunophenotypes appeared typical of patients with ALL, although there may have been an excess number of patients who lacked the common ALL antigen (CALLA, or CD 10). In 17 patients studied, the leukemia cells were positive for CALLA in 11 (65 percent) and of B-cell lineage in 13 (76 percent). The subtype of leukemia according to the French—American—British classification was L1 in 14 patients, L2 in 3, and indeterminate in 1.
Two patients had bulky disease at diagnosis (Patients 3 and 4) and met the criteria of the Children's Cancer Study Group for leukemia—lymphoma syndrome.8 Both had a large mediastinal mass, a relatively high hemoglobin level, and a T-cell phenotype. Patient 19 also had leukemia—lymphoma syndrome. All three of these patients were male and less than 18 years old and had homozygous interferon-gene deletions. Two other patients, who had hemizygous deletions, had T-cell disease with a mediastinal mass less than one third the diameter of the chest and did not meet the criteria for leukemia—lymphoma syndrome. These results suggest a possible association between leukemia—lymphoma syndrome and homozygous interferon-gene deletion.
Treatment was administered according to the protocols of the Children's Cancer Study Group (11 patients), the Cancer and Leukemia Group B (3 patients), the Southwestern Oncology Group (1 patient), or local institutions (3 patients). All 18 patients had a complete remission; however, 3 required two to three months of induction therapy (Patients 5, 8, and 18), whereas the others entered remission within one month. Eleven patients (61 percent) are alive at the time of this writing and have been followed up for 12 to 45 months since diagnosis (median, 25); only 8 patients (44 percent) remain in a continuous complete remission. Over half the patients with interferon-gene deletions have relapsed; however, all of these belong to groups with an unfavorable prognosis on the basis of having an age of less than 1 year or more than 10 years, a white-cell count above 100×109, or a T-cell phenotype. Among the 10 patients who relapsed, the site of first relapse was the bone marrow in 8, the central nervous system in 1, and the testes in 1.
Discussion
The observation of homozygous or hemizygous deletions of the interferon genes in the primary leukemia cells from 29 percent of patients with ALL demonstrates that genetic lesions of this region of chromosome 9 are more prevalent among patients with ALL than previously indicated by cytogenetic studies.1 2 3 4 The finding that the peripheral-blood cells obtained from Patient 1 during remission had a normal complement of interferon genes shows that, in this patient, the deletion was a feature associated with leukemia rather than a constitutional defect. Other neoplastic diseases, such as melanoma9 and glioblastoma,10 have a high incidence of 9p abnormalities that may also be associated with interferon-gene deletions.
In this study we could not find an association of interferon-gene deletion with a particular age group, sex, immunophenotype, or other clinical or laboratory characteristic, and we do not have evidence that interferon-gene deletion is independently associated with a poor outcome. Prospective studies of a large consecutive series of patients will be needed to determine the prognostic importance of interferon-gene deletions.
The incidence of homozygous interferon-gene deletions in the patients' cell samples — 6.4 percent —is substantially lower than that observed in ALL-derived cell lines — 23.0 percent6 (and Diaz MO: unpublished data). It is possible that cells that lack a relevant gene contained in the deleted segment are more easily established as cell lines in vitro. A comparison of the visible deletions of 9p observed in either cell lines or primary leukemia cells from patients with ALL suggested that the minimal region of overlap was band 9p22 (Fig. 3Figure 3
Segments of 9p Lost as a Consequence of Visible Deletions or Unbalanced Translocations in Leukemia Cells That Also Have a Deletion of Interferon-αa Genes and the lnterferonβ31 Gene.). Some deletions that extend proximally on 9p from band p22 include the interferon-α genes, but not the interferon-β1 gene. These results indicate that the interferon-β1 gene is distal to the remainder of the interferon-gene cluster, which agrees with the results of the analysis of t(9:l1) (p22;q23) in cases of acute monocytic leukemia.11 A complete deficiency of the enzyme methylthioadenosine phosphorylase (MTAP) has been detected in several neoplastic cell lines, including leukemiaderived cell lines,6 , 12 , 13 as well as in samples of primary leukemia cells.14 , 15 We observed a complete deficiency of this enzyme in each of six leukemia cell lines that had homozygous deletions of the interferon genes.6 In two studies of primary leukemia cells, a deficiency of MTAP was found in 10 percent of patients with acute leukemia and in 15.0 percent of patients with ALL.14 , 15 A gene responsible for the function of MTAP has been mapped to 9pter–ql2 by Carrera et al.16 This gene is likely to be lost as a result of most of the visible and submicroscopic deletions of 9p that are observed in ALL, and therefore it may be located within 9p22, the minimal region of overlap of the chromosomal deletions.
The frequent association between ALL and specific visible or submicroscopic chromosomal abnormalities that lead to the loss of genetic material from 9p suggests that the loss of a tumor-suppressor gene may be involved in the pathogenesis of this disease. Chromosome 9 is preferentially lost from tumorigenic lines of hybrid cells prepared by fusing transformed mouse cells and normal human fibroblasts.17 , 18 The proximal half of mouse chromosome 4, which is partially syntenic with human chromosome 9, including the region of the interferon genes, is also preferentially lost from tumors induced by injecting somatic cell hybrids prepared from tumorigenic and nontumorigenic mouse cells into syngeneic hosts.19 , 20 In rats, chromosome 5, which is also partially syntenic with human chromosome 9, contains a gene that suppresses anchorage independence in mouse-hepatoma—rat-fibroblast cell hybrids.21 In this case, the suppressor activity has been mapped to bands q22 and q23 of rat chromosome 5, close to the interferon-α1 gene.
Because of the known actions of interferons on cell proliferation and differentiation,22 which in some cases are mediated by an autocrine mechanism,23 , 24 one or more of the interferon genes could be the relevant deleted elements, whose loss releases lymphoid cells from the normal constraints on their proliferation. Some of the deletions affect only the interferon-α genes, suggesting that the interferon-βl gene is not the relevant gene. In Patient 4, we observed the deletion of all but two of the interferon-α genes, which were hemizygous, indicating that one of the chromosome breaks occurred within this gene cluster. Leukemia cells with hemizygous deletions retain a haploid set of the interferon genes; in these cases, a complete deletion of one or some of the interferon genes is unlikely to be the critical event in leukemogenesis. However, the remaining allele (or alleles) of the relevant interferon gene (or genes) may be inactivated by point mutations or small structural rearrangements or by an epigenetic mechanism such as DNA methylation. A gene-dosage effect is another possible explanation.
Alternatively, the deletions may include a leukemia suppressor gene — not an interferon gene, but a gene closely linked to them. In patients with hemizygous deletions, the putative tumor-suppressor gene on the normal chromosome 9 may be inactivated by mutation or by a smaller deletion that excludes the interferon genes. The identification of cell lines with normal interferon genes but with a complete deficiency of MTAP activity6 provides support for this hypothesis. MTAP activity is present in several leukemia-cell samples and cell lines with hemizygous deletions of the interferon genes6 (and Chilcote R, Diaz MO: unpublished data), suggesting that MTAP is not the relevant gene.
In conclusion, we have shown that deletions of the interferon genes are relatively frequent in primary leukemia cells from patients with ALL (29 percent), and that approximately half these deletions are submicroscopic. The minimal region of deletion is band 9p22; thus, the interferon genes are likely to be located in this band. Our data indicate that the order of the interferon genes on 9p is as follows: pter, interferonβ1, interferon-α gene cluster, cen. We propose that the loss of a leukemia suppressor gene, either one of the interferon-α genes or an unrelated but closely linked gene, may be the relevant genetic defect in these deletions, and that this defect may be associated with the leukemogenic process in ALL.
Supported by grants (CA-49133 [Dr. Diaz] and CA-42557 [Dr. Rowley]) from the National Cancer Institute, by a Clinical Oncology Career Development Award (Dr. Larson) from the American Cancer Society, by the Schweppes Foundation, and by the University of Chicago Cancer Research Center. Dr. Rubin is a Pew Scholar in the Biomedical Sciences and a Special Fellow of the Leukemia Society of America; Dr. Le Beau is a Scholar of the Leukemia Society of America.
We are indebted to Dr. P. Pitha and Dr. C. Schneider for providing the cloned gene probes used in these studies, to Dr. R. Chilcote and Dr. S. Smith for allowing us to use unpublished data, and to the many physicians from other hospitals in the Chicago area who provided clinical and laboratory information on some of the patients studied.
Source Information
From the Section of Hematology/Oncology, Department of Medicine (M.O.D., C.M.R., A.H., S.Z., R.A.L., M.M.L.B., J.D.R.), and the Department of Pediatrics (C.M.R.), University of Chicago. Address reprint requests to Dr. Diaz at the University of Chicago, Department of Medicine, 5841 S. Maryland Ave., Box 420, Chicago, IL 60637.
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