30 results on '"Thirman, M J"'
Search Results
2. A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes
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Locke, F, Agarwal, R, Kunnavakkam, R, van Besien, K, Larson, R A, Odenike, O, Godley, L A, Liu, H, Le Beau, M M, Gurbuxani, S, Thirman, M J, Sipkins, D, White, C, Artz, A, and Stock, W
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- 2013
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3. Results from the phase 2 RESONATE (TM)-17 Trial: Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic leukaemia with 17p deletion
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Munir, T., O'Brien, S., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C., Osterborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., Ilhan, O., Keating, M., Call, T. G., Brown, J. R., Stevens-Brogan, M., Li, Y., Clow, F., James, D., Chu, A., Hallek, M., Stilgenbauer, S., Munir, T., O'Brien, S., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C., Osterborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., Ilhan, O., Keating, M., Call, T. G., Brown, J. R., Stevens-Brogan, M., Li, Y., Clow, F., James, D., Chu, A., Hallek, M., and Stilgenbauer, S.
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- 2015
4. Results from the phase 2 RESONATE (TM)-17 trial: Efficacy and safety of Ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma with Del17p
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Stilgenbauer, S., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C., Osterborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., Ilhan, O., Keating, M., Call, T. G., Brown, J. R., Stevens-Brogan, M., Li, Y., Clow, F., James, D. F., Chu, A. D., Hallek, M., O'Brien, S., Stilgenbauer, S., Jones, J. A., Coutre, S. E., Mato, A. R., Hillmen, P., Tam, C., Osterborg, A., Siddiqi, T., Thirman, M. J., Furman, R. R., Ilhan, O., Keating, M., Call, T. G., Brown, J. R., Stevens-Brogan, M., Li, Y., Clow, F., James, D. F., Chu, A. D., Hallek, M., and O'Brien, S.
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- 2015
5. Regulation of MEIS1 by distal enhancer elements in acute leukemia
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Wang, Q-f, primary, Li, Y-j, additional, Dong, J-f, additional, Li, B, additional, Kaberlein, J J, additional, Zhang, L, additional, Arimura, F E, additional, Luo, R T, additional, Ni, J, additional, He, F, additional, Wu, J, additional, Mattison, R, additional, Zhou, J, additional, Wang, C-z, additional, Prabhakar, S, additional, Nobrega, M A, additional, and Thirman, M J, additional
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- 2013
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6. PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas
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Baron, B. W., primary, Anastasi, J., additional, Hyjek, E. M., additional, Bies, J., additional, Reddy, P. L., additional, Dong, J., additional, Joseph, L., additional, Thirman, M. J., additional, Wroblewski, K., additional, Wolff, L., additional, and Baron, J. M., additional
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- 2012
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7. Unexplained Anemia Predominates Despite an Intensive Evaluation in a Racially Diverse Cohort of Older Adults From a Referral Anemia Clinic
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Artz, A. S., primary and Thirman, M. J., additional
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- 2011
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8. Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia.
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Thirman, M J, primary, Levitan, D A, additional, Kobayashi, H, additional, Simon, M C, additional, and Rowley, J D, additional
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- 1994
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9. Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis.
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Thirman, M J, primary, Albrecht, J H, additional, Krueger, M A, additional, Erickson, R R, additional, Cherwitz, D L, additional, Park, S S, additional, Gelboin, H V, additional, and Holtzman, J L, additional
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- 1994
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10. Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations.
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McCabe, N. R., primary, Burnett, R. C., additional, Gill, H. J., additional, Thirman, M. J., additional, Mbangkollo, D., additional, Kipiniak, M., additional, van Melle, E., additional, Ziemin-van der Poel, S., additional, Rowley, J. D., additional, and Diaz, M. O., additional
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- 1992
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11. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.
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DiNardo, C. D., Jonas, B. A., Pullarkat, V., Thirman, M. J., Garcia, J. S., Wei, A. H., Konopieva, M., Döhner, H., Letai, A., Fenaux, P., Koller, E., Havelange, V., Leber, B., Esteve, J., Wang, J., Pejsa, V., Hájek, R., Porkka, K., Illés, Á., and Lavie, D.
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ACUTE myeloid leukemia , *AZACITIDINE , *FEBRILE neutropenia , *OLDER patients , *PLACEBOS - Abstract
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase lb study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidinevenetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; PcO.OOl). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 29%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax- azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.). [ABSTRACT FROM AUTHOR]
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- 2020
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12. The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis.
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Luo RT, Lavau C, Du C, Simone F, Polak PE, Kawamata S, and Thirman MJ
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- Amino Acid Sequence, Animals, Cell Transformation, Neoplastic genetics, Cells, Cultured, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase, Leukemia etiology, Mice, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Sequence Alignment, Transcriptional Elongation Factors, DNA-Binding Proteins genetics, Leukemia genetics, Neoplasm Proteins, Peptide Elongation Factors, Proto-Oncogenes, Transcription Factors genetics
- Abstract
The MLL-ELL chimeric gene is the product of the (11;19)(q23p13.1) translocation associated with de novo and therapy-related acute myeloid leukemias (AML). ELL is an RNA polymerase II elongation factor that interacts with the recently identified EAF1 (ELL associated factor 1) protein. EAF1 contains a limited region of homology with the transcriptional activation domains of three other genes fused to MLL in leukemias, AF4, LAF4, and AF5q31. Using an in vitro transformation assay of retrovirally transduced myeloid progenitors, we conducted a structure-function analysis of MLL-ELL. Whereas the elongation domain of ELL was dispensable, the EAF1 interaction domain of ELL was critical to the immortalizing properties of MLL-ELL in vitro. To confirm these results in vivo, we transplanted mice with bone marrow transduced with MLL fused to the minimal EAF1 interaction domain of ELL. These mice all developed AML, with a longer latency than mice transplanted with the wild-type MLL-ELL fusion. Based on these results, we generated a heterologous MLL-EAF1 fusion gene and analyzed its transforming potential. Strikingly, we found that MLL-EAF1 immortalized myeloid progenitors in the same manner as that of MLL-ELL. Furthermore, transplantation of bone marrow transduced with MLL-EAF1 induced AML with a shorter latency than mice transplanted with the MLL-ELL fusion. Taken together, these results indicate that the leukemic activity of MLL-ELL requires the EAF1 interaction domain of ELL, suggesting that the recruitment by MLL of a transactivation domain similar to that in EAF1 or the AF4/LAF4/AF5q31 family may be a critical common feature of multiple 11q23 translocations. In addition, these studies support a critical role for MLL partner genes and their protein-protein interactions in 11q23 leukemogenesis.
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- 2001
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13. EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein.
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Simone F, Polak PE, Kaberlein JJ, Luo RT, Levitan DA, and Thirman MJ
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- Amino Acid Sequence, Animals, Histone-Lysine N-Methyltransferase, Humans, Mice, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Precipitin Tests, Protein Binding, Sequence Alignment, Transcription Factors isolation & purification, Transcriptional Activation, Transcriptional Elongation Factors, Transfection, Tumor Cells, Cultured, DNA-Binding Proteins drug effects, DNA-Binding Proteins metabolism, Oncogene Proteins, Fusion pharmacology, Peptide Elongation Factors, Proto-Oncogenes, Transcription Factors metabolism
- Abstract
The (11;19)(q23;p13.1) translocation in acute leukemia leads to the generation of a chimeric protein that fuses MLL to the transcriptional elongation factor ELL. A novel protein was isolated from a yeast 2-hybrid screen with ELL that was named EAF1 for ELL-associated factor 1. Using specific antibodies, the endogenous EAF1 and ELL proteins were coimmunoprecipitated from multiple cell lines. In addition, endogenous EAF1 also exhibited the capacity to interact with ELL2. Database comparisons with EAF1 identified a region with a high content of serine, aspartic acid, and glutamic acid residues that exhibited homology with the transcriptional activation domains of several translocation partner proteins of MLL, including AF4, LAF4, and AF5q31. A similar transcriptional activation domain has been identified in this region of EAF1. By confocal microscopy, endogenous EAF1 and ELL colocalized in a distinct nuclear speckled pattern. Transfection of the MLL-ELL fusion gene delocalized EAF1 from its nuclear speckled distribution to a diffuse nucleoplasmic pattern. In leukemic cell lines derived from mice transplanted with MLL-ELL-transduced bone marrow, EAF1 speckles were not detected. Taken together, these data suggest that expression of the MLL-ELL fusion protein may have a dominant effect on the normal protein-protein interactions of ELL.
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- 2001
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14. Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice.
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Lavau C, Luo RT, Du C, and Thirman MJ
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- Acute Disease, Animals, Gene Transfer Techniques, Genetic Vectors, Histone-Lysine N-Methyltransferase, Leukemia, Myeloid etiology, Mice, Myeloid-Lymphoid Leukemia Protein, Retroviridae, Transcriptional Elongation Factors, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins genetics, Hematopoietic Stem Cells pathology, Hematopoietic Stem Cells physiology, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Neoplasm Proteins, Oncogene Proteins, Fusion genetics, Peptide Elongation Factors, Proto-Oncogenes, Transcription Factors genetics
- Abstract
The MLL-ELL fusion gene results from the translocation t(11;19)(q23;p13.1) that is associated with de novo and therapy-related acute myeloid leukemia. To study its transforming properties, we retrovirally transduced primary murine hematopoietic progenitors and assessed their growth properties both in vitro and in vivo. MLL-ELL increased the proliferation of myeloid colony-forming cells in methylcellulose cultures upon serial replating, whereas overexpression of ELL alone had no effect. We reconstituted lethally irradiated congenic mice with bone marrow progenitors transduced with MLL-ELL or the control MIE vector encoding the enhanced green fluorescent protein. When the peripheral blood of the mice was analyzed 11-13 weeks postreconstitution, we found that the engraftment of the MLL-ELL-transduced cells was superior to that of the MIE controls. At this time point, the contribution of the donor cells was normally distributed among the myeloid and nonmyeloid compartments. Although all of the MIE animals (n = 10) remained healthy for more than a year, all of the MLL-ELL mice (n = 20) succumbed to monoclonal or pauciclonal acute myeloid leukemias within 100-200 days. The leukemic cells were readily transplantable to secondary recipients and could be established as immortalized cell lines in liquid cultures. These studies demonstrate the enhancing effect of MLL-ELL on the proliferative potential of myeloid progenitors as well as its causal role in the genesis of acute myeloid leukemias.
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- 2000
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15. Developmental analysis and subcellular localization of the murine homologue of ELL.
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Thirman MJ, Diskin EB, Bin SS, Ip HS, Miller JM, and Simon MC
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- Acute Disease, Amino Acid Sequence, Animals, Cloning, Molecular, Conserved Sequence, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Embryo, Mammalian chemistry, Embryonic and Fetal Development, Fluorescent Antibody Technique, Indirect, In Situ Hybridization, Leukemia, Myeloid etiology, Liver chemistry, Mice, Molecular Sequence Data, Neoplasm Proteins genetics, RNA Polymerase II metabolism, RNA, Messenger analysis, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Species Specificity, Transcription Factors genetics, Transcription Factors metabolism, Transcriptional Elongation Factors, Cell Compartmentation, DNA-Binding Proteins isolation & purification, Neoplasm Proteins isolation & purification, Peptide Elongation Factors, Transcription Factors isolation & purification
- Abstract
The ELL gene was first identified by its involvement with MLL in the translocation (11;19)(q23;p13.1) in acute myeloid leukemia. To date, nine other MLL partner genes have been cloned, but their precise functions have yet to be determined. To characterize the functions of ELL further, we have cloned the murine homologue of ELL and have found that the gene is highly conserved at the nucleotide and amino acid level. The open reading frame of the murine homologue contains 602 aa, slightly smaller than the 621 aa in the human gene. With Northern blot analysis, a 3.4-kb transcript is detected in all tissues examined with greatest levels of expression in the liver. Unlike human ELL, only a single transcript can be detected with either murine coding sequence or 3' untranslated region probes. To examine the spatial and temporal pattern of expression in murine development, in situ hybridization studies were performed with sense and antisense riboprobes from the 3' untranslated region of murine Ell. Ell is expressed diffusely by embryonic day 7.5 (E7.5). In addition, high levels of expression can be detected in maternally derived decidual tissue. At E14.5, Ell is expressed diffusely throughout the embryo. However by E16.5, specific expression in the liver and gastrointestinal tract becomes prominent and remains so in both neonates and adults. To determine the subcellular localization of ELL, we developed a polyclonal antiserum to ELL that was used for immunofluorescence studies in COS-7, HeLa, NIH 3T3, and A7r5 cells. The ELL protein was localized to the nucleus but excluded from nucleoli in all cell lines examined. Recently, the gene product of ELL was found to function as an RNA polymerase II elongation factor, an activity that is consistent with our immunofluorescence data. Thus, these studies extend our understanding of the normal functions of ELL and provide additional insight into its aberrant function when fused to MLL in acute myeloid leukemia.
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- 1997
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16. Analysis of the t(6;11)(q27;q23) in leukemia shows a consistent breakpoint in AF6 in three patients and in the ML-2 cell line.
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Tanabe S, Zeleznik-Le NJ, Kobayashi H, Vignon C, Espinosa R 3rd, LeBeau MM, Thirman MJ, and Rowley JD
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- Adolescent, Adult, Amino Acid Sequence, Base Sequence, Cell Line, Chromosome Mapping, Cloning, Molecular, DNA, Complementary, DNA-Binding Proteins genetics, Histone-Lysine N-Methyltransferase, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 6, Leukemia, Myeloid, Acute genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Proto-Oncogenes, Transcription Factors, Translocation, Genetic
- Abstract
The t(6;11)(q27;23) is one of the most common translocations observed in patients with acute myeloid leukemia (AML). The translocation breakpoint involves the MLL gene, which is the human homolog of the Drosophila trithorax gene, at 11q23 and the AF6 gene at 6q27. Reverse transcriptase-polymerase chain reaction (RT-PCR) using an MLL sense primer and an AF6 antisense primer detected the MLL/AF6 fusion cDNA from three leukemia patients with the t(6;11) [two AML and one T-acute lymphoblastic leukemia (ALL)] and one cell line. The fusion point in the AF6 cDNA from these cases is identical, regardless of the leukemia phenotype. The ML-2 cell line, which was established from a patient with AML that developed after complete remission of T-cell lymphoma, has retained an 11q23-24 deletion from the lymphoma stage and has acquired the t(6;11) with development of AML. The ML-2 cells have no normal MLL gene on Southern blot analysis, which indicates that an intact MLL gene is not necessary for survival of leukemic cells.
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- 1996
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17. Therapy-related myeloid leukemia.
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Thirman MJ and Larson RA
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- Acute Disease, Antineoplastic Agents adverse effects, Bone Marrow Transplantation adverse effects, Humans, Leukemia, Myeloid genetics, Myelodysplastic Syndromes genetics, Neoplasms, Second Primary genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma etiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Radiotherapy adverse effects, Leukemia, Myeloid etiology, Myelodysplastic Syndromes etiology, Neoplasms, Second Primary etiology
- Abstract
One of the most serious possible consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can be distinguished currently. These include classic therapy-related myeloid leukemia, leukemia that follows treatment with agents that inhibit topoisomerase II, acute lymphoblastic leukemia, and leukemias with 21q22 rearrangements or inv(16) or t(15;17). These types of leukemia are discussed in detail in this article.
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- 1996
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18. Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: correlation with scaffold attachment regions and topoisomerase II consensus binding sites.
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Broeker PL, Super HG, Thirman MJ, Pomykala H, Yonebayashi Y, Tanabe S, Zeleznik-Le N, and Rowley JD
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- Acute Disease, Adolescent, Adult, Antineoplastic Agents, Phytogenic adverse effects, Antineoplastic Agents, Phytogenic therapeutic use, Base Sequence, Binding Sites, Centromere ultrastructure, Child, Child, Preschool, Consensus Sequence, DNA, Neoplasm genetics, Etoposide adverse effects, Etoposide therapeutic use, Female, Histone-Lysine N-Methyltransferase, Humans, Infant, Leukemia chemically induced, Male, Middle Aged, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Neoplasms, Second Primary chemically induced, Telomere ultrastructure, Teniposide adverse effects, Teniposide therapeutic use, Topoisomerase II Inhibitors, Tumor Cells, Cultured, Chromatin ultrastructure, Chromosomes, Human, Pair 11 ultrastructure, DNA Topoisomerases, Type II metabolism, DNA-Binding Proteins genetics, Leukemia genetics, Neoplasms, Second Primary genetics, Proto-Oncogenes, Transcription Factors, Translocation, Genetic
- Abstract
A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.
- Published
- 1996
19. Abnormalities of chromosome band 11q23 and the MLL gene in pediatric myelomonocytic and monoblastic leukemias. Identification of the t(9;11) as an indicator of long survival.
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Martinez-Climent JA, Espinosa R 3rd, Thirman MJ, Le Beau MM, and Rowley JD
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- Adolescent, Adult, Child, Child, Preschool, Chromosome Banding, DNA, Neoplasm analysis, Female, Gene Rearrangement genetics, Histone-Lysine N-Methyltransferase, Humans, In Situ Hybridization, Fluorescence, Infant, Leukemia, Monocytic, Acute mortality, Leukemia, Monocytic, Acute pathology, Leukemia, Myelomonocytic, Acute mortality, Leukemia, Myelomonocytic, Acute pathology, Male, Myeloid-Lymphoid Leukemia Protein, Survival Analysis, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 9, DNA-Binding Proteins genetics, Leukemia, Monocytic, Acute genetics, Leukemia, Myelomonocytic, Acute genetics, Proto-Oncogenes, Transcription Factors, Translocation, Genetic
- Abstract
Purpose and Methods: We reviewed the cytogenetic pattern of the malignant cells in 36 patients who were < 20 years of age and who had M4 and M5 leukemias, excluding M4Eo cases with inv(16). We performed fluorescence in situ hybridization (FISH) and molecular studies to determine the actual incidence of 11q23/MLL abnormalities in these patients., Results: Eighteen patients had 11q23 translocations or insertions detected by cytogenetic analysis (15 cases) or by FISH (3 cases); 10 patients had t(9;11), all of whom had M5a. Eight patients had other 11q23 translocations or insertions not involving chromosome 9[t(11q23)] (four each had M4 or M5 leukemias). Eighteen cases with M4/M5 did not have 11q23 abnormalities. MLL rearrangements were found in all patients with translocations or insertions of 11q23 who were studied. Clinically, children with t(9;11) were indistinguishable from other patients with M4-M5 leukemias. In contrast, the t(11q23) group was characterized by extreme hyperleukocytosis, CNS disease, and skin involvement. Patients with the t(9;11) had a better outcome when compared with patients in the t(11q23) group (EFS +/- SE at 3 years, 56 +/- 17% versus 10 +/- 10%, p = 0.04), and to all the remaining children with M4-M5 leukemias (p = 0.04)., Conclusions: The combination of cytogenetic, FISH, and molecular analysis provides a highly sensitive strategy for detection of 11q23/MLL gene rearrangements in childhood M4-M5 leukemias. Our more precise classification of these patients allows a more accurate correlation with outcome. The favorable prognostic significance of the t(9;11) should be confirmed in prospective studies including a larger number of children as well as adults.
- Published
- 1995
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20. Detection of 11q23/MLL rearrangements in infant leukemias with fluorescence in situ hybridization and molecular analysis.
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Martinez-Climent JA, Thirman MJ, Espinosa R 3rd, Le Beau MM, and Rowley JD
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- Chromosome Banding, Chromosome Disorders, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 19, Female, Histone-Lysine N-Methyltransferase, Humans, In Situ Hybridization, Fluorescence, Infant, Infant, Newborn, Male, Myeloid-Lymphoid Leukemia Protein, Translocation, Genetic, Zinc Fingers, Chromosome Aberrations pathology, DNA-Binding Proteins genetics, Leukemia pathology, Proto-Oncogenes, Transcription Factors
- Abstract
Cytogenetic abnormalities of band 11q23 have been found in more than 50% of infant leukemias regardless of the phenotype. Using probes for the MLL gene at 11q23, MLL rearrangements have been identified in 70-80% of all infant leukemias including virtually all of the cases with 11q23 translocations, as well as cases with apparently normal karyotypes. We reviewed the chromosomal pattern of 26 cases of infant leukemias (12 ALL, 12 AML, two AUL). Eleven had 11q23 translocations, five had other abnormalities, and 10 had a normal karyotype. To determine whether 11q23/MLL rearrangements were present in the leukemia cells of patients with a normal karyotype, we performed FISH and molecular studies of eight of these patients who had adequate material. Three were found to have 11q23/MLL abnormalities, two of them detected by FISH; one ALL case had a t(11;19) (q23;p13.3), and one AML case had a t(11;19) (q23;p13.1). Retrospective review confirmed the presence of the t(11;19) in a small percentage of poor quality metaphase cells in both cases. A rearrangement of the MLL gene was detected by Southern blot analysis of leukemic cells from a third patient with ALL; one cell with a deletion of 11q23 was found on karyotypic review. Therefore, in our series the actual incidence of 11q23 abnormalities in infant leukemias was 54% (14/26): 67% in ALL (8/12) and 50% in AML (6/12). Our findings suggest that most infant leukemias with apparently normal karyotypes that have a molecular rearrangement of the MLL gene are undetected subtle translocations.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
21. U937 cell line has a t(10;11)(p13-14;q14-21) rather than a deletion of 11q.
- Author
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Kobayashi H, Thirman MJ, and Rowley JD
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- Humans, In Situ Hybridization, Fluorescence, Tumor Cells, Cultured, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 11, Gene Deletion, Translocation, Genetic
- Abstract
The U937 cell line was studied with the fluorescence in situ hybridization (FISH) technique using phage and cosmid probes which were mapped and ordered on 11q. Although this cell line was thought to have a del(11q), FISH demonstrated that 11q was translocated to 10p and that the breakpoint on 11q is centromeric to the MLL gene. This 10;11 translocation appears to be a t(10;11)(p13-14;q14-21), which was recently reported to be a recurring translocation in malignant hematologic disease. This cell line will be a good tool for the study of this chromosomal rearrangement.
- Published
- 1995
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22. Detection of MLL gene rearrangements in adult acute lymphoblastic leukemia. A Cancer and Leukemia Group B study.
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Stock W, Thirman MJ, Dodge RK, Rowley JD, Diaz MO, Wurster-Hill D, Sobol RE, Davey FR, Larson RA, and Westbrook CA
- Subjects
- Adolescent, Adult, Aged, Chromosome Disorders, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, DNA, Neoplasm genetics, Female, Gene Rearrangement, Histone-Lysine N-Methyltransferase, Humans, Male, Middle Aged, Myeloid-Lymphoid Leukemia Protein, Translocation, Genetic, Zinc Fingers, Chromosome Aberrations genetics, DNA-Binding Proteins genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogenes, Transcription Factors
- Abstract
Specific structural rearrangements involving chromosome band 11q23 occur in a variety of hematologic malignancies, including an estimated 2-7% of patients with acute lymphoblastic leukemia (ALL). Translocations involving chromosome band 11q23 have been associated with a poor prognosis in patients with ALL. Recently, a gene known as MLL has been identified which is involved in acute lymphoid and myeloid leukemias with rearrangements at 11q23. A 0.74-kilobase (kb) cDNA probe from the MLL gene can detect both common and uncommon rearrangements involving MLL on conventional Southern blots. We studied 86 newly diagnosed adults entered on an ALL clinical trial to investigate the incidence of MLL gene rearrangements and to determine clinical, morphologic, immunologic and cytogenetic characteristics of such patients. Two of 86 patients had MLL gene rearrangements detected by Southern blot analysis. One of these 86 patients had an 11q23 translocation by cytogenetic analysis whereas the second patient was unevaluable by standard cytogenetic analysis. Southern blot identification of rearrangements involving MLL, especially in patients with limited material for cytogenetic analysis, can provide critical diagnostic and prognostic information which may be useful in the clinical management of patients with these abnormalities.
- Published
- 1994
23. Molecular analysis of the T-cell acute lymphoblastic leukemia-associated t(1;7)(p34;q34) that fuses LCK and TCRB.
- Author
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Burnett RC, Thirman MJ, Rowley JD, and Diaz MO
- Subjects
- Base Sequence, Chromosome Mapping, Cloning, Molecular, Codon, DNA Primers, Humans, Introns, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Molecular Sequence Data, Polymerase Chain Reaction, Promoter Regions, Genetic, RNA Splicing, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 7, Leukemia-Lymphoma, Adult T-Cell genetics, Protein-Tyrosine Kinases genetics, Receptors, Antigen, T-Cell, alpha-beta genetics, Translocation, Genetic
- Abstract
Previously we had characterized the t(1;7)(p34;q34) translocation from HSB-2. This translocation fused the beta T-cell receptor gene (TCRB) constant region and transcriptional enhancer with the type I transcription unit of the LCK gene on the derivative 1 [der(1)] chromosome. The type II promoter was translocated to the der(7) chromosome. Regarding the mechanism of the t(1;7) in HSB-2, we identified an alternating purine-pyrimidine tract (G-T)17 at the 1p34/LCK breakpoint. Additionally, sequence analysis of both breakpoint junctions provided data that implicate the V(D)J recombinase in formation of the t(1;7). A heptamer-nonamer recognition sequence with a 12-bp spacer was found in the immediate vicinity of the 1p34/LCK breakpoint and, thus, chromosomal breakage at 1p34 may be explained as resulting from recombinase activity. Because phosphorylation of Tyr-505 in vivo regulates the tyrosine kinase activity of p56lck we amplified a region from LCK exon 12 that contains the codon for Tyr-505 and showed no mutation of this codon in HSB-2 DNA and, therefore, p56lck in HSB-2 is not activated by mutation of Tyr-505. We have analyzed LCK gene expression in HSB-2 and SUP-T12 cell lines. RNase protection analysis identified almost exclusively type I transcripts in HSB-2. An independent t(1;7) in SUP-T12 also resulted in the juxtaposition of LCK to TCRB. The breakpoint in SUP-T12 occurred 2 kb 5' of the type II promoter, leaving an intact LCK gene on the der(1) chromosome. RNase protection analysis identified both type I and type II LCK transcripts in a 3:1 ratio in SUP-T12. Factors other than proximity to the TCRB enhancer must affect promoter utilization in this cell line.
- Published
- 1994
24. Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II.
- Author
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Super HJ, McCabe NR, Thirman MJ, Larson RA, Le Beau MM, Pedersen-Bjergaard J, Philip P, Diaz MO, and Rowley JD
- Subjects
- Adult, Aged, Chromosome Mapping, DNA, Neoplasm isolation & purification, Female, Humans, Lymphoma genetics, Male, Middle Aged, Myelodysplastic Syndromes genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Restriction Mapping, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chromosomes, Human, Pair 11, Gene Rearrangement, Genetic Markers, Leukemia, Myeloid chemically induced, Leukemia, Myeloid genetics, Neoplasms drug therapy, Topoisomerase II Inhibitors
- Abstract
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.
- Published
- 1993
25. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
- Author
-
Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, and Sandberg AA
- Subjects
- Acute Disease, Adolescent, Child, Child, Preschool, DNA, Neoplasm genetics, Female, Humans, Lymphoma genetics, Lymphoma, Non-Hodgkin genetics, Male, Tumor Cells, Cultured, Chromosomes, Human, Pair 11, Gene Rearrangement, Leukemia, Myeloid genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic
- 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 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-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.
- Published
- 1993
- Full Text
- View/download PDF
26. Do terminal deletions of 11q23 exist? Identification of undetected translocations with fluorescence in situ hybridization.
- Author
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Kobayashi H, Espinosa R 3rd, Thirman MJ, Fernald AA, Shannon K, Diaz MO, Le Beau MM, and Rowley JD
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Child, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Leukemia genetics, Male, Myelodysplastic Syndromes genetics, Chromosome Deletion, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 6, Translocation, Genetic
- Abstract
Fluorescence in situ hybridization (FISH) was performed on bone marrow or peripheral blood cells thought to contain a del(11)(q23q25) from four patients who had acute leukemia or myelodysplasia. Cells from all patients were shown to contain translocations that involved chromosome 6 in three of them. Our data suggest that a large proportion of presumptive del(11)(q23) or del(11)(q23q25) chromosomes may represent previously unidentified translocations that can be detected by FISH.
- Published
- 1993
- Full Text
- View/download PDF
27. Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization.
- Author
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Kobayashi H, Espinosa R 3rd, Thirman MJ, Gill HJ, Fernald AA, Diaz MO, Le Beau MM, and Rowley JD
- Subjects
- Adolescent, Adult, Anemia, Refractory, with Excess of Blasts genetics, CD3 Complex genetics, Child, Child, Preschool, Chromosome Mapping, DNA Probes, Female, Humans, Infant, Leukemia, Lymphoid genetics, Leukemia, Myeloid genetics, Male, Middle Aged, Translocation, Genetic, Chromosome Aberrations, Chromosomes, Human, Pair 11, In Situ Hybridization, Fluorescence, Leukemia genetics
- Abstract
Twenty-four patients whose cells contained a variety of 11q23 rearrangements, including translocations, insertions, and an inversion, were studied using fluorescence in situ hybridization with cosmid, phage, and plasmid probes mapped to 11q22-24. In 17 patients, the breakpoints of the common 11q23 translocations involving chromosomes 4, 6, 9, and 19 as well as some uncommon translocations involving 3q23, 17q25, 10p11, and an insertion 10;11 were all located in the breakpoint cluster region of the MLL gene, regardless of age, phenotype of disease, or involvement of a third chromosome. The breakpoints in 11q23 in the other 7 patients with a t(7;11)(p15;q23), inv(11)(p11q23), t(4;11)(q23;q23), der(5)t(5;11)(q13;q23), ins(10;11)(p11;q23q24), t(11;14)(q23;q11), or t(11;18;11) (p15;q21;q23) were located either centromeric to CD3D or telomeric to THY1. Thus, although most 11q23 rearrangements, involve the same breakpoint cluster region of MLL, there is heterogeneity in the breakpoint in some of the rare rearrangements.
- Published
- 1993
28. Variability of 11q23 rearrangements in hematopoietic cell lines identified with fluorescence in situ hybridization.
- Author
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Kobayashi H, Espinosa R 3rd, Thirman MJ, Davis EM, Diaz MO, Le Beau MM, and Rowley JD
- Subjects
- Cell Line, Chromosome Mapping, DNA Probes, Gene Rearrangement, Humans, In Situ Hybridization, Translocation, Genetic, Chromosomes, Human, Pair 11, Hematopoietic Stem Cells ultrastructure
- Abstract
We mapped and ordered 17 cosmid, phage, and plasmid clones to chromosome 11, bands q22-q24, using fluorescence in situ hybridization (FISH). We then analyzed four hematopoietic cell lines with 11q23 rearrangements, Karpas 45, SUP-T13, RC-K8, and Karpas 422, using these probes. The studies showed that the translocation breakpoints of the Karpas 45 and SUP-T13 cell lines, which were derived from T-cell malignancies, were located in the same breakpoint cluster region of the MLL gene as the RS4; 11 cell line and patients with the t(9;11), t(11;19), and t(6;11) described previously. We confirmed that the translocation breakpoint of the RC-K8 cell line was located telomeric to the MLL gene, and found that the derivative 11 chromosome of the Karpas 422 cell line, which had been thought to contain a t(4;11) (q21;q23), was in fact formed through a deletion and an inverted tandem repeat of part of 11q.
- Published
- 1993
29. Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation.
- Author
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Thirman MJ, Devine SM, O'Toole K, Cizek G, Jessurun J, Hertz M, and Geller RB
- Subjects
- Adult, Bronchiolitis Obliterans drug therapy, Graft vs Host Disease etiology, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive surgery, Leukemia, Myeloid, Chronic-Phase surgery, Male, Pneumonia drug therapy, Prednisone therapeutic use, Syndrome, Transplantation, Homologous, Bone Marrow Transplantation adverse effects, Bronchiolitis Obliterans etiology, Pneumonia etiology
- Abstract
We report a patient who underwent two allogeneic bone marrow transplants for chronic myelogenous leukemia, initially in 1984 and again after relapse in 1990, who developed an identical pulmonary syndrome at a similar interval following each transplant. The patient presented with a non-productive cough, bilateral inspiratory crackles, and multiple patchy infiltrates on chest X-ray. Pulmonary function testing revealed a restrictive abnormality but no obstructive defects. The appearance of this pulmonary disorder after each transplant coincided with the development of chronic graft-versus-host disease. In both instances, this pulmonary syndrome completely reversed with corticosteroid therapy. The patient's chest computed tomographic scan and lung biopsy specimens were consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia (BOOP). While bronchiolitis obliterans has been reported following allogeneic transplant, BOOP has not previously been reported in this setting.
- Published
- 1992
30. Neurotoxicity of meperidine.
- Author
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Goetting MG and Thirman MJ
- Subjects
- Administration, Oral, Adult, Female, Hamartoma surgery, Humans, Kidney Neoplasms surgery, Meperidine metabolism, Myoclonus chemically induced, Emergencies, Meperidine adverse effects, Seizures chemically induced
- Abstract
Meperidine neurotoxicity manifests as shakiness, tremors, myoclonus, and seizures. It is generally seen with repeated parenteral use. We report a case of meperidine neurotoxicity from oral use by an otherwise healthy woman. The pharmacology and clinical implications are discussed.
- Published
- 1985
- Full Text
- View/download PDF
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