Original Article
Rearrangement of the MLL Gene in Acute Lymphoblastic and Acute Myeloid Leukemias with 11q23 Chromosomal Translocations
N Engl J Med 1993; 329:909-914September 23, 1993
- Abstract
Background
Translocations involving chromosome band 11q23 are very frequent in both acute lymphoblastic and acute myeloid leukemias and are the most common genetic alteration in infants with leukemia. In all age groups and all phenotypes of leukemia, an 11q23 translocation carries a poor prognosis. A major question has been whether one or several genes on band 11q23 are implicated in these leukemias. Previously, we identified the chromosomal breakpoint region in leukemias with the common 11q23 translocations and subsequently cloned a gene named MLL that spans the 11q23 breakpoint.
Methods
We isolated a 0.74-kb BamHI fragment from a complementary DNA (cDNA) clone of the MLL gene. To determine the incidence of MLL rearrangements in patients with 11q23 abnormalities, we analyzed DNA from 61 patients with acute leukemia, 3 cell lines derived from such patients, and 20 patients with non-Hodgkin's lymphoma and 11q23 aberrations.
Results
The 0.74-kb cDNA probe detected DNA rearrangements in the MLL gene in 58 of the patients with leukemia, in the 3 cell lines, and in 3 of the patients with lymphoma. All the breaks occurred in an 8.3-kb breakpoint cluster region within the MLL gene. The probe identified DNA rearrangements in all 48 patients with the five common 11q23 translocations involving chromosomes 4, 6, 9, and 19, as well as in 16 patients with uncommon 11q23 aberrations. Twenty-one different chromosomal breakpoints involving the MLL gene were detected.
Conclusions
MLL gene rearrangements were detected with a single probe and a single restriction-enzyme digest in all DNA samples from patients with the common 11q23 translocations as well as in 16 patients or cell lines with other 11q23 anomalies. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation.
Media in This Article
Figure 1
The Breakpoint Cluster Region of the MLL Gene.Figure 2
Results of Southern Blotting of DNA from Patients with AML, ALL, or Lymphoma.Article Activity
- Article
The molecular analysis of recurring structural abnormalities of chromosomes in human neoplasia has led to the identification of a number of genes involved in these rearrangements. Alterations in these genes are implicated in the development of malignant conditions. For example, in chronic myelogenous leukemia, the proto-oncogene ABL is translocated from chromosome 9 to the BCR gene on chromosome 22, leading to the generation of a chimeric gene and a fusion protein1. In lymphoid cancers, translocations frequently involve the immunoglobulin or T-cell-receptor genes, which are juxtaposed to critical oncogenes, causing their abnormal expression2. Recently, many of the chromosomal translocation junctions in acute myeloid leukemia (AML) have been cloned, and all result in chimeric genes with aberrant functions3.
Translocations involving the chromosome band 11q23 occur frequently in hematologic cancers, affecting 7 to 10 percent of acute lymphoblastic leukemias (ALLs), with the (4;11) and (11;19) translocations predominating, and 5 to 6 percent of AMLs, with the (6;11), (9;11), and (11;19) translocations being the most common4-8. Translocations involving 11q23 are the single most common cytogenetic abnormality in infants with acute leukemia, regardless of the phenotype9,10. They account for approximately 70 percent of all cases of both AML and ALL in infants. These translocations are also observed in therapy-related leukemias, especially in patients previously treated with inhibitors of topoisomerase II. Flow cytometry may reveal the expression of myeloid or monocytoid markers in addition to B-cell lymphoid markers in patients with ALL11. Typically, patients with AML have acute myelomonocytic leukemia (AML-M4) or acute monoblastic leukemia (AML-M5), and they may express lymphoid markers in addition to myeloid markers12,13. These observations suggest that rearrangements of a gene at 11q23 may affect a pluripotential progenitor cell that is capable of either myeloid or lymphoid differentiation. Alternatively, a mechanism for differentiation that is shared by both lymphoid and myelomonocytic stem cells may be deregulated as a consequence of these translocations.
Patients with AML and ALL who have 11q23 translocations have aggressive clinical features and often present with hyperleukocytosis and early involvement of the central nervous system. An 11q23 translocation in both AML and ALL confers a very poor prognosis. In the report of the Sixth International Workshop on Chromosomes in Leukemia, there were no long-term survivors among patients with ALL and the (4;11) translocation, whereas patients with AML and translocations involving 11q had a long-term disease-free survival rate of 3 percent14. Thus, the detection of the gene involved in these translocations might be the critical first step in identifying patients who require intensive therapy and designing new treatment strategies based on the molecular genetic consequences of these translocations.
We identified a yeast artificial chromosome that contained the breakpoint region in leukemias with several common 11q23 translocations15. Subsequently, we cloned a gene named MLL (for mixed-lineage leukemia or myeloid-lymphoid leukemia) that spans the breakpoint on 11q2316. Several groups have cloned and sequenced the same gene and have called it Htrx, ALL-1, and HRX17-19. The strong homology between the zinc-finger region of MLL and the Drosophila trithorax gene suggests that the MLL gene has been evolutionarily conserved. The MLL gene has multiple large transcripts in the range of 13 to 15 kb and is transcribed in a centromere-to-telomere direction20. The involved genes on chromosomes 4 and 19 have been identified; the translocations with 11q23 in these patients result in fusion transcripts18,19.
A major question in the analysis of leukemias with 11q23 aberrations is whether a single oncogene or a group of oncogenes is involved in each translocation subtype and whether there is heterogeneity among the common subtypes. In addition, a large number of rare translocations involving 11q23 have been identified, but their relation to the common 11q23 translocations has not been determined. We have identified a single complementary DNA (cDNA) probe from the MLL gene that could detect rearrangements in DNA digested with a single enzyme from all leukemias with the common 11q23 translocations, as well as those with rare chromosomal anomalies with a breakpoint at band 11q23.
Methods
Patients and Cell Lines
Samples of bone marrow, lymph nodes, or peripheral blood were obtained at the University of Chicago Medical Center, Saitama Cancer Center, Southwest Biomedical Research Institute, and Memorial Sloan-Kettering Cancer Center. Samples from 61 patients with acute leukemia and 20 patients with lymphoma were selected on the basis of a karyotype containing an 11q23 abnormality and the availability of cryopreserved samples of leukemic bone marrow or peripheral blood. In the patients with lymphoma, cytogenetic and molecular analyses were performed on lymph-node samples.
The DNA from three cell lines was also analyzed. The cell line RS4;11 was derived from a patient with B-cell ALL and was a gift from J. Kersey, University of Minnesota21; SUP-T13 was derived from a patient with T-cell ALL and was a gift from S. Smith, University of Chicago22; and Karpas 45 was derived from a patient with T-cell ALL and was a gift from A. Karpas, Cambridge University23.
Cytogenetic Analysis
Cytogenetic analysis was performed with a trypsin-Giemsa banding technique. Chromosomal abnormalities were described according to the International System for Human Cytogenetic Nomenclature24. Fluorescence in situ hybridization was performed as previously described15.
cDNA Library
A cDNA library was prepared from a monocytic cell line as described by McCabe et al20. The library was screened with probes from the centromeric and telomeric ends of a 14-kb genomic fragment of BamHI (clone 14), and several cDNA clones were obtained and mapped with restriction endonucleases.
Molecular Analysis
DNA was extracted from cryopreserved cells and digested with restriction enzymes, subjected to electrophoresis on 0.7 percent agarose gels, transferred to nylon membranes, and hybridized with radiolabeled cDNA probes at 42 °C. All DNA blots were washed in 1 × saline sodium citrate buffer (0.15 M sodium chloride, 0.015 M sodium citrate) and 1 percent sodium dodecyl sulfate at 65 °C before autoradiography was performed.
Results
We isolated a 0.74-kb BamHI fragment from a cDNA subclone of MLL. This fragment was composed of exons located at the centromeric and telomeric ends of an 8.3-kb genomic BamHI fragment of the MLL gene as well as exons dispersed along the genomic fragment (Figure 1Figure 1
The Breakpoint Cluster Region of the MLL Gene.). We detected rearrangements of the MLL gene on Southern blot analysis in 61 patients (58 with leukemia and 3 with lymphoma) and 3 cell lines by using the 0.74-kb cDNA fragment as a probe (Figure 2Figure 2Results of Southern Blotting of DNA from Patients with AML, ALL, or Lymphoma.). The probe identified rearrangements in all 48 samples of DNA (from 46 patients and 2 cell lines) with the common translocations involving 11q23 (Table 1Table 1
DNA Rearrangements Detected with the 0.74-kb cDNA Probe in 46 Patients with Leukemia and Common 11q23 Translocations.). We also identified similar MLL gene rearrangements in DNA from 10 patients and 1 cell line with several less common 11q23 translocations listed by Mitelman et al.25,26 as well as from 5 other patients with 11q23 anomalies not reported by Mitelman et al (Table 2Table 2
DNA Rearrangements Detected with the 0.74-kb cDNA Probe in 12 Patients with Leukemia and 1 Leukemic Cell Line with Uncommon 11q23 Aberrations.). Rearrangements were detected in the three cell lines with 11q23 translocations -- RS4;11, SUP-T13, and Karpas 45. In approximately 75 percent of patients with DNA rearrangements, two rearranged bands were identified, and in 25 percent only one rearranged band was present. The probe did not detect rearrangements in samples from patients in remission who had rearrangements in the DNA from their leukemic cells. In addition, rearrangements were not identified in three patients with rare 11q23 translocations involving chromosome bands 4q23, 5q13, and 10p13. Two of these three patients and several of the patients with lymphoma have recently been studied with fluorescence in situ hybridization and were found to have breakpoints on 11q23 far from the MLL gene27.The age distribution of the patients with leukemia in whom DNA rearrangements were detected was broad: 11 patients were 1 year old or younger, 16 were 2 to 16 years of age, and 31 were 17 years of age or older. There were 27 female and 31 male patients. The samples from the 28 patients with ALL and 30 with AML were indistinguishable on Southern blot analysis with the use of our probe.
We also examined 20 patients with non-Hodgkin's lymphoma and detected rearrangements in 3: 1 with follicular small-cleaved-cell lymphoma, 1 with Burkitt's lymphoma, and 1 with a diffuse mixed-cell lymphoma (Table 3Table 3
DNA Rearrangements Detected with the 0.74-kb cDNA Probe in Three Patients with Non-Hodgkin's Lymphoma with 11q23 Anomalies.). In addition to an 11q23 aberration, the patients with follicular lymphoma and Burkitt's lymphoma also had the cytogenetic abnormalities that are characteristic of these diseases (Table 3). The other 17 patients with lymphoma and 11q23 abnormalities, primarily deletions and duplications, had no rearrangements identified by our cDNA probe, presumably because the breakpoints did not involve MLL.Discussion
Although it has long been recognized that there are a variety of recurring 11q23 aberrations in leukemia and lymphoma, the specific location of these breakpoints has not been identified. A major question has been whether one or several oncogenes might be implicated in the pathogenesis of these hematologic cancers, given their diverse phenotypes and multiple translocation partners. Previous investigators have reported conflicting results because of the unavailability of specific DNA probes28,29. Because chromosome band 11q23 contains approximately 10,000 kb of DNA, the clarification of this issue has required the use of techniques that permit increasing precision in the localization of breakpoints30-36.
We have previously used fluorescence in situ hybridization to localize the breakpoint of the common 11q23 translocations to a region of 330 kb. In the current study, we used Southern blot analysis to provide evidence that all the leukemias with the common 11q23 translocations and the majority with rare aberrations involve the rearrangement of a single, recently identified gene, MLL. Thus, MLL is one of the oncogenes most frequently involved in hematologic cancers.
We identified DNA rearrangements in 61 patients and 3 cell lines with 11q23 abnormalities and delineated an 8.3-kb breakpoint cluster region within the MLL gene by using a 0.74-kb BamHI cDNA fragment as a probe. The probe identified DNA rearrangements in all patients with the common translocations as well as in 16 with less common aberrations. No heterogeneity was detectable on Southern blot analysis within each cytogenetic subtype or among the different subtypes of 11q23 translocations. Using the probe, we also identified three patients with lymphoma who had the same breakpoint as the patients with leukemia and common 11q23 translocations.
In molecular diagnostic studies of cancer, multiple probes and several enzyme digests are often necessary to establish or rule out the involvement of a specific oncogene. In this study, we found that the use of a single probe and a single enzyme digest was sufficient to detect all MLL gene rearrangements, an important point in patients with limited material for cytogenetic analysis. Moreover, recent studies have shown a higher rate of detection of gene rearrangements, such as the Philadelphia chromosome, with molecular probes than with cytogenetic methods37.
Cytogenetic and molecular genetic analyses of leukemias are often critical in establishing a diagnosis that can be used to select specific therapy. For example, in acute promyelocytic leukemia, which is characterized by the (15;17) translocation, the use of all-trans-retinoic acid has led to a high rate of complete remission38. Because patients with leukemia with 11q23 translocations have an extremely poor prognosis with standard treatment regimens, the ability to detect an MLL gene rearrangement might allow the identification of patients who would benefit from more aggressive therapy. This is likely to be particularly important in infants with leukemia, because 70 percent have a rearrangement of the MLL gene, whether or not an 11q23 translocation is detected on cytogenetic analysis39. Current protocols have adopted the approach of stratifying patients to treatment regimens on the basis of cytogenetic or molecular genetic criteria40. Patients with a high risk of relapse, such as those with MLL gene rearrangements, may be advised to undergo intensive chemotherapy and allogeneic bone marrow transplantation.
The spectrum of diseases that involve the MLL gene is unique among hematologic cancers in that rearrangements of the same gene have been identified in ALL and AML as well as in low- and high-grade non-Hodgkin's lymphomas. In hematologic cancers, translocations that lead to the formation of chimeric genes are usually limited to one partner; for example, BCR and ABL are only involved in the (9;22) translocation in chronic myelogenous leukemia. Rarely, alternative translocation partners have been identified; the (8;21) and (3;21) translocations have both been found to generate fusion genes involving the AML1 gene on chromosome 2141. Remarkably, we identified 21 different chromosomal regions associated with MLL in 11q23 aberrations. This exceeds the number of different genetic partners, identified over the past 20 years, that involve the immunoglobulin and T-cell-receptor genes. The identification of MLL gene rearrangements represents an important step in the isolation of a series of new genes involved in these leukemias and lymphomas.
Cimino et al. have described a 0.48-kb DdeI genomic fragment that detected rearrangements in a 5.8-kb region in 26 of 30 patients (87 percent) with the (4;11), (9;11), and (11;19) translocations42,43. They hypothesized that the breaks in the DNA from the other four patients, which were not identified by the probe, occurred either at another site within the gene or at other loci in 11q23. The breakpoint cluster region that we identified encompasses a slightly larger region of 8.3 kb and contains the breakpoints in all leukemias with the common translocations as well as many with rare translocations.
Although the majority of 11q23 translocations involve MLL, molecular studies showed that the 11q23 band contains breakpoints for at least three other cancer-related translocations. Studies of the RCK8 B-cell lymphoma line have led to the identification of a gene called RCK that is 300 kb telomeric to MLL44,45. In addition, we cloned an 11q23 translocation from a patient with a null-cell ALL whose breakpoint is also telomeric to MLL and RCK46. Recently, the PLZF gene, cloned from a patient with acute promyelocytic leukemia and a variant (11;17) translocation, was shown to be centromeric to MLL27,47.
The MLL gene appears to be critically involved in leukemia and lymphoma. The 0.74-kb cDNA probe should be useful in cloning the breakpoints of cancers that involve MLL, in the identification of new genes, and in further molecular analysis of these translocations. This probe may also have broad clinical application, since all gene rearrangements can be detected with a single probe and a single enzyme digest. This probe may also be of value in monitoring the response to chemotherapy and assessing residual disease after treatment. In both childhood and adult leukemias, this may allow earlier detection of a high-risk group that requires aggressive treatment.
Presented in part at the annual meeting of the American Society of Hematology, Anaheim, Calif., December 4-8, 1992.
Supported in part by grants from the National Institutes of Health (CA42557 to Dr. Rowley; CA40046 to Drs. Larson, Le Beau, and Rowley; CA38725 to Dr. Diaz; and CA34775 to Dr. Chaganti), a grant from the Department of Energy (DE-FG02-86ER60408 to Dr. Rowley), a grant from the Spastic Paralysis Research Foundation, Illinois-Eastern Iowa District of Kiwanis International (to Drs. Rowley and Diaz), a National Cancer Institute Environmental Carcinogenesis Training Grant (5T32 CA09273-12 to Dr. Burnett), and a Basic Research Training in Medical Oncology Grant (5T32CA09566 to Dr. Thirman). Dr. Le Beau is a Scholar of the Leukemia Society of America. Dr. Thirman is a recipient of a Young Investigator Award from the American Society of Clinical Oncology.
We are indebted to Paul Gardner, Rafael Espinosa III, and Elizabeth van Melle for their technical assistance.
Source Information
From the Section of Hematology and Oncology, Departments of Medicine (M.J.T., R.C.B., D.M., H.K., R.A.L., M.M.L., M.O.D., J.D.R.), Molecular Genetics and Cell Biology (H.J.G., S.Z.P., J.D.R.), and Pediatrics (N.R.M.), University of Chicago, Chicago; the Saitama Cancer Center, Saitama, Japan (Y.K.); Southwest Biomedical Research Institute and Genetrix, Inc., Scottsdale, Ariz. (R.M., A.A.S.); and Memorial Sloan-Kettering Cancer Center, New York (R.S.K.C.).
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