Rodman Morgan

Rearrangement of the MLL Gene in Acute Lymphoblastic and Acute Myeloid Leukemias with 11q23 Chromosomal Translocations

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 DAN (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-Hodgkins 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.

BCL3 rearrangements and t(14;19) in chronic lymphocytic leukemia and other B-cell malignancies: A molecular and cytogenetic study

The t(14;19)(q32.3;q13.1) is a recurring translocation found in the neoplastic cells of some patients with chronic lymphocytic leukemia (CLL) or other B‐lymphocytic neoplasms. We previously cloned the translocation breakpoint junctions present in the leukemic cells from three such patients and identified a gene, BCL3, whose transcription is increased as a result of the translocation. In the present paper, we describe three additional patients with the t(14;19), one with lymphoma and two with CLL, and report the cloning and sequencing of the breakpoint junction in one of these patients as well as in a previously reported patient. We and others have found that the breakpoints on chromosome 14, with one exception, fall within the switch region upstream of the immunoglobulin heavy chain Cα1 or Cα2 sequences. Several of the breaks within chromosome 19 fall immediately upstream of the BCL3 gene, but several others are more than 16 kb 5′ of the gene. Most patients with CLL and the t(14;19) also show trisomy 12. Genes Chromosom. Cancer 20:64–72, 1997.

Trisomy 4: An entity within acute nonlymphocytic leukemia☆

Trisomy 4 is a newly recognized primary chromosome change in leukemia. Five cases of acute nonlymphocytic leukemia (ANLL) are described from the United States and France. As in cases from Belgium, the only chromosome abnormality detected in the leukemic cells was trisomy 4. This was associated preferentially with ANLL of the M4 type (by FAB classification): acute myelomonocytic leukemia.

Chromosome clues to acute leukemia in Down's syndrome☆

Surprisingly few cases of Downs syndrome with acute leukemia have been documented by chromosome banding studies of the leukemia cells. We studied a Downs syndrome child with acute myelomonocytic leukemia and found that, including this case, only 24 cases of Downs syndrome and acute leukemia have been reported with chromosome banding analysis. Twenty-three of the patients had a trisomy 21 chromosome complement, whereas, one had a translocation. The types of acute leukemia included acute myeloblastic leukemia, acute myelomonocytic leukemia, acute monoblastic leukemia, acute lymphoblastic leukemia, and erythroleukemia. Only three cases had chromosomes missing from the leukemic cells. Sixteen of the 24 patients had extra chromosomes in their malignant cells. Chromosomes #8 and #21 were extra in six cases each and chromosomes #19 and #22 were extra in four cases each. Chromosome rearrangements were observed in nine cases. Three of the nine cases had partial deletion of the long arm of chromosome #6. Cases of Downs syndrome with acute leukemia need to be reported with high-resolution chromosome banding of the leukemia cells. There is as yet no clear chromosome clue as to the precise basis of the etiologic association between Downs syndrome and acute leukemia.

Application of fluorescence in situ hybridization in hematological disorders

In the present study, chromosome changes in bone marrow (BM) or peripheral blood (PB) cells from 13 patients with malignant hematologic disorders were analyzed by classical cytogenetic techniques (G-banding) and fluorescence in situ hybridization (FISH) procedures using centromere specific probes for chromosomes 1, 6, 7, 8, 9, 12, 18, 13/21, and X, and a DNA probe specific for the long arm of chromosome Y. The cytogenetic data obtained with G-banding were in accord with those obtained by FISH to metaphase chromosomes. Most significantly, FISH to interphase nuclei offered reliable results and in some cases provided important information concerning crucial chromosome anomalies which were not or could not be completely detected by analyzing metaphase chromosomes. Our results indicate that FISH could be clinically valuable in five major areas: 1) marker chromosome identification; 2) identification of trisomy consistent with certain specific hematological neoplasms; 3) clonal evaluation post observation of a single cell with trisomy; 4) clonal evaluation post-sex-mismatched bone marrow transplantation (BMT); and 5) residual disease detection following clinical remission.

Fragile sites: Overview, occurrence in acute nonlymphocytic leukemia and effects of caffeine on expression

Interest has recently grown in the possible role of chromosomal fragile sites as factors predisposing to chromosome rearrangements characteristic of specific human cancers. Data from two series of experiments relating to this hypothesis are presented. First, the effects of caffeine and theophylline on expression of the fragile X and common fragile sites was studied in lymphocytes from three subjects. Caffeine and theophylline did not enhance fragile X expression under the conditions employed but did greatly enhance expression of the common fragile sites. Second, three patients with acute nonlymphocytic leukemia-M4 and inv(16)(p13q22) in leukemic cells were tested for the presence of fra(16)(q22) in normal cells. The fragile site was not seen in any of the patients in this study.

Telomeric fusion in pre-T-cell acute lymphoblastic leukemia

SummaryTelomeric fusion, a rare phenomenon, was observed in malignant cells from the peripheral blood of an 18-year-old male with rapidly progressive pre-T-cell acute lymphoblastic leukemia (ALL). Only two comparable cases, both with B-cell ALL, have been reported with telomeric fusion in neoplasia. All of the leukemic cells examined from our patient had two chromosome abnormalities consisting of partial triplication (trp) of chromosome 2 and a derivative chromosome 3. Approximately a third of the leukemic cells showed in addition telomere-telomere fusions. These involved the telomeric regions of 1p, 2p, 4q, 5q, 7q, 10q, 11q, 12p, 15p, 21p, and Xq and 3p of the derivative (3). The findings in this case suggest that telomeric fusion may function as a mechanism for the development of chromosome rearrangements that may play a role, albeit rarely, in human neoplasia.

Identification of complex t(15;17) in APL by FISH

Fluorescence in situ hybridization (FISH) provides a sensitive and effective approach in identifying the RAR-alpha/PML fusion event in acute promyelocytic leukemia (APL) with the t(15;17). In the present study we describe the use of this assay for the identification of the RAR-alpha/PML fusion in bone marrow (BM) cells from three APL patients with complex t(15;17) translocations.

Deletion of chromosome band 13q14: a primary event in preleukemia and leukemia.

Chromosome abnormalities were analyzed in 200 consecutive patients with preleukemia and leukemia, and four patients were found with a deletion of 13q14 for an incidence of 2%. Together with data on chromosome aberrations in cancer from the literature, our results indicate clearly that deletion of band 13q14 is a nonrandom chromosome anomaly in premalignant and malignant blood disorders. Deletion of 13q14 appears specifically to constitute a primary event in the initiation of preleukemia. An additional rearrangement involving another chromosome must occur for progression of the preleukemia to acute nonlymphocytic leukemia.

Acute myeloblastic leukemia (AML) with t(6;9) (p23;q34): A specific subgroup of AML?

A case of acute myeloblastic leukemia (AML) of M2 type in the FAB classification without Auer bodies in the leukemic cells was shown to have t(6;9)(p23;q34) in the marrow cells. Four hematologically similar cases with identical karyotype changes have been published. We propose, in support of others, that this may constitute a subgroup of AML characterized by a translocation between chromosome #6 and #9.