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1.
Bone Marrow Transplant ; 57(1): 106-112, 2022 01.
Article in English | MEDLINE | ID: mdl-34671121

ABSTRACT

We evaluated the impact on survival of antithymocyte globulin conditioning (TLI-ATG) with radiation (RT) boost to high risk or residual disease before allogeneic hematopoietic cell transplant (allo-HCT) for adults with lymphoma (excluding mycosis fungoides and low-grade NHL other than SLL/CLL). Of 251 evaluable patients, 36 received an RT boost within 3 months of allo-HCT at our institution from 2001 to 2016. At the time of TLI-ATG, patients who received boost vs no boost had a lower rate of CR (11% vs 47%, p = 0.0003), higher rates of bulky disease (22% vs 4%, p < 0.0001), extranodal disease (39% vs 5%, p < 0.0001), and positive PET (75% vs 28%, p < 0.00001). In the boost group, the median (range) largest axial lesion diameter was 5.2 cm (1.8-22.3). Median follow-up was 50.2 months (range: 1-196). There was no significant difference in OS, time to recurrence, or time to graft failure with vs without boost. A trend toward higher percent donor CD3+ chimerism was seen with vs without boost (p = 0.0819). The worst boost-related toxicity was grade 2 dermatitis. RT boost may help successfully mitigate the risk of high risk or clinically evident residual disease in adults with lymphoma undergoing allo-HCT.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Lymphoma , Adult , Antilymphocyte Serum , Humans , Lymphoma/therapy , Neoplasm, Residual , Transplantation Conditioning , Transplantation, Homologous
3.
Bone Marrow Transplant ; 50(10): 1286-92, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26146806

ABSTRACT

We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).


Subject(s)
Antilymphocyte Serum/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Non-Hodgkin/therapy , Transplantation Conditioning/methods , Transplantation, Autologous/adverse effects , Transplantation, Homologous/methods , Adult , Cohort Studies , Female , Humans , Male , Middle Aged , Young Adult
4.
Am J Transplant ; 15(3): 695-704, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25693475

ABSTRACT

Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients.


Subject(s)
Chimerism , Graft Survival , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Living Donors , Adult , Cohort Studies , Female , Humans , Male , Middle Aged , Young Adult
6.
Am J Transplant ; 12(5): 1133-45, 2012 May.
Article in English | MEDLINE | ID: mdl-22405058

ABSTRACT

Sixteen patients conditioned with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA-matched donors in a tolerance induction protocol. Blood cell monitoring included changes in chimerism, balance of T-cell subsets and responses to donor alloantigens. Fifteen patients developed multilineage chimerism without graft-versus-host disease (GVHD), and eight with chimerism for at least 6 months were withdrawn from antirejection medications for 1-3 years (mean, 28 months) without subsequent rejection episodes. Four chimeric patients have just completed or are in the midst of drug withdrawal, and four patients were not withdrawn due to return of underlying disease or rejection episodes. Blood cells from all patients showed early high ratios of CD4+CD25+ regulatory T cells and NKT cells versus conventional naive CD4+ T cells, and those off drugs showed specific unresponsiveness to donor alloantigens. In conclusion, TLI and ATG promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and hematopoietic donor cell infusions. All 16 patients had excellent graft function at the last observation point with or without maintenance drugs.


Subject(s)
Graft Survival/immunology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Transplantation Immunology , Adult , Antilymphocyte Serum/therapeutic use , Blood Group Incompatibility , Female , Fluorescent Antibody Technique , Graft vs Host Disease/immunology , Humans , Immune Tolerance , Lymphatic Irradiation , Male , Middle Aged , Transplantation Chimera , Treatment Outcome , Young Adult
7.
Bone Marrow Transplant ; 47(4): 516-21, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21602899

ABSTRACT

Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.


Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Carmustine/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation , Melphalan/administration & dosage , Multiple Myeloma , Transplantation Conditioning/methods , Adolescent , Adult , Aged , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Survival Rate , Time Factors , Transplantation, Autologous
8.
Bone Marrow Transplant ; 47(4): 581-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21552302

ABSTRACT

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.


Subject(s)
Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Mycophenolic Acid/analogs & derivatives , Sirolimus/administration & dosage , Transplantation Conditioning , Unrelated Donors , Acute Disease , Adolescent , Adult , Child , Child, Preschool , Female , Follow-Up Studies , Graft vs Host Disease/mortality , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Humans , Immunosuppressive Agents , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Transplantation, Homologous
9.
Bone Marrow Transplant ; 46(2): 192-9, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20498648

ABSTRACT

Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20-60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0 mg/kg (days -8 to -5), etoposide 60 mg/kg (day -4), CY 60 mg/kg (day -2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n=41), CML in second chronic phase or blast crisis (n=8), myelofibrosis and myeloproliferative disorders (n=8), and myelodysplasia (n=39). Thirty-six percent (n=35) of patients received BM whereas 64% (n=61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6-14.6 years) actuarial 5-year OS was 32% (95% CI 22-42) and 5-year EFS was 31% (95% CI 21-41). Relapse rate was 24% (95% CI 15-33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20-38) at day 100 and 38% (95% CI 29-47) at 1 year. Cumulative incidence of acute (grade II-IV) and extensive chronic GVHD was 27% (95% CI 18-36) and 29% (95% CI 18-40), respectively. There was no statistically significant difference in OS (31 vs 32%, P=0.89) or relapse rates (17 vs 28%, P=0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.


Subject(s)
Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/surgery , Leukemia, Myeloid, Acute/surgery , Transplantation Conditioning , Adult , Busulfan/administration & dosage , Busulfan/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cytomegalovirus/physiology , Etoposide/administration & dosage , Etoposide/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Middle Aged , Treatment Outcome , Virus Activation
10.
Bone Marrow Transplant ; 45(2): 303-9, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19597427

ABSTRACT

Patients with diffuse large B-cell lymphoma (DLBCL) who do not achieve a complete response to front-line combination chemotherapy are often offered high-dose therapy and autologous hematopoietic cell transplantation (AHCT). However, the efficacy of this therapy in this patient population has been addressed in only a few published reports. We retrospectively analyzed the outcomes of patients with a diagnosis of de novo DLBCL who underwent AHCT at our center between 1988 and 2002, and identified 43 consecutive patients who had not achieved a CR before AHCT, although most showed at least a partial response (PR) to either induction or subsequent salvage chemotherapy. A total of 15 patients received a conditioning regimen that included high-dose chemotherapy with fractionated TBI (FTBI), whereas 28 patients received high-dose chemotherapy only. All autografts were treated ex vivo with MoAbs and complement in an effort to remove any residual malignant B cells. A total of 33 (77%) patients achieved a CR after AHCT. With a median follow-up of 7.3 years, the 5-year OS was 69% and EFS was 59%. Four patients died from non-relapse mortality. By univariate analyses, the following characteristics did not significantly impact OS: disease stage at diagnosis, age-adjusted IPI (International Prognostic Index) score, age > or =40 years, earlier radiotherapy and the use of FTBI in the conditioning regimen. These results confirm the long-term efficacy of AHCT for patients with DLBCL after induction failure.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Large B-Cell, Diffuse/therapy , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Remission Induction , Retrospective Studies , Rituximab , Transplantation Conditioning/methods , Transplantation, Autologous , Treatment Outcome
11.
Oncogene ; 26(11): 1586-94, 2007 Mar 08.
Article in English | MEDLINE | ID: mdl-16953217

ABSTRACT

RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.


Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Insulin-Like Growth Factor I/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Nuclear Proteins/antagonists & inhibitors , Signal Transduction , Transcription Factors/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Histone-Lysine N-Methyltransferase , Histones/chemistry , Histones/metabolism , Humans , Insulin-Like Growth Factor I/genetics , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Lysine/metabolism , Methylation , Nuclear Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic , Transcription Factors/metabolism
13.
Eur J Haematol ; 67(5-6): 318-21, 2001.
Article in English | MEDLINE | ID: mdl-11872080

ABSTRACT

A 59-yr-old man developed fevers, shortness of breath, persistent cough and weight loss, shortly after initiation of therapy with interferon-alpha 2a and cytosine arabinoside for treatment of chronic myelogenous leukemia. Radiologic pulmonary infiltrates and lung tissue biopsy were consistent with bronchiolitis obliterans organizing pneumonia (BOOP). After discontinuation of the chemotherapeutic drugs, the pneumonic symptoms and chest roentgenogram infiltrates resolved. This report suggests that treatment with interferon-alpha, in combination with cytosine arabinoside, may produce the rare complication of BOOP.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cryptogenic Organizing Pneumonia/chemically induced , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cryptogenic Organizing Pneumonia/diagnostic imaging , Cytarabine/administration & dosage , Cytarabine/adverse effects , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Male , Middle Aged , Radiography , Recombinant Proteins
14.
Blood ; 95(5): 1767-72, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10688836

ABSTRACT

High-frequency microsatellite instability (MSI), defined as more than 20% unstable loci, is an inconsistent finding in hematologic malignancies; consequently, the significance of deficient DNA mismatch repair (MMR) to their pathogenesis has been questioned. To further investigate the relationship between MMR deficiency and genomic instability in hematologic malignancies, this study evaluated MSH2-/- murine lymphomas for insertion/deletion (ID) mutations within the transforming growth factor (TGF)-beta receptor type II (TbetaR-II) gene and MSI at 10 neutral microsatellites. The lymphomas displayed ID mutations within short mononucleotide runs of TbetaR-II at a high frequency, whereas nonmalignant tissue from corresponding animals lacked mutations. Loss of TbetaR-II transcripts and protein was seen in 6 of 7 murine lymphomas harboring acquired TbetaR-II mutations. In the analysis of paired nonmalignant and tumor DNA samples, low-frequency but not high-frequency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 12 displayed microsatellite stability. MSI was even less frequent in nonmalignant tissue as only 3 of 20 samples displayed low-frequency MSI and 17 displayed stability. Evaluation of 20 single cell clones from the MSH2-/- lymphoma cell lines R25 and L15 identified high-frequency MSI in 4 and 2 clones, respectively. The remaining clones showed low-frequency MSI or stability. These findings suggest that acquired TbetaR-II mutations represent important inactivating events in tumor pathogenesis following MSH2 deficiency. Furthermore, for some hematolymphoid malignancies, the evaluation of cancer-associated genes for ID mutations may represent a more sensitive marker of MMR deficiency than evaluation of neutral microsatellites for high-frequency MSI. (Blood. 2000;95:1767-1772)


Subject(s)
DNA Repair/genetics , DNA-Binding Proteins , Lymphoma, T-Cell/genetics , Microsatellite Repeats , Mutagenesis, Insertional , Neoplasm Proteins/physiology , Proto-Oncogene Proteins/physiology , Receptors, Transforming Growth Factor beta/genetics , Sequence Deletion , Animals , DNA, Neoplasm/genetics , Mice , Mice, Knockout , MutS Homolog 2 Protein , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Receptor, Transforming Growth Factor-beta Type II
15.
Hematology ; 5(3): 177-187, 2000.
Article in English | MEDLINE | ID: mdl-11399613

ABSTRACT

Combination high-dose cytosine arabinoside (ARA-C) and daunorubicin (DNR) for primary remission induction of patients with acute myeloblastic leukemia (AML) was evaluated in a single institution study. Patients aged 55 or less with an HLA-sibling received an allogeneic bone marrow transplant (alloBMT) in first remission; other responders were offered autologous BMT (autoBMT). For remission induction 93 patients aged less than 60 received DNR 45 mg/m(2) BSA x 3 and ARA-C 2 gm/m(2) BSA every 12 hours for 12 doses; 53 aged 60 or older DNR 25 mg/m(2) daily x 3 and ARA-C 1.5-2.0 gm/m(2) BSA every 12 hours for 12 doses. Consolidation doses of DNR were the same but ARA-C 100 mg/m(2) BSA/day x 5 was given by continuous intravenous infusion. The complete remission rate for patients less than 60 years was 69.9% (95% CI: 59.5-79.0%) and 47.2% (95% CI: 33.3-61.4%) for the older patients. The median duration of first remission for the younger patients was 13.0 months and of overall survival 17.9 months; for patients over 60 years 5.6 and 10.0 months respectively. Disease-free survival and overall survival of the 19 patients receiving alloBMT and the 13 patients undergoing autoBMT aged less than 55 years and in first or second complete remission were significantly increased compared with 22 patients in remission but not having BMT (p < 0.001 and p < 0.013). The results support the effectiveness of high-dose ARA-C for remission induction, a need for intensive consolidation therapy and a role for BMT in the management of AML.

16.
Transplantation ; 66(9): 1251-3, 1998 Nov 15.
Article in English | MEDLINE | ID: mdl-9825825

ABSTRACT

BACKGROUND: We report a case of intestinal graft-versus-host disease (GVHD) in a syngeneic bone marrow transplant patient. METHODS: Several days after receiving a bone marrow transplant from his identical twin for treatment of non-Hodgkin's lymphoma, a 47-year-old man developed a skin rash and diarrhea. RESULTS: A colonic biopsy on day +15 revealed characteristic changes of acute intestinal GVHD. Molecular studies (microsatellite DNA and HLA sequence-specific primer polymerase chain reaction analyses) confirmed the genotypic identity of donor and host and the improbability of transfusion-associated GVHD. CONCLUSION: This case illustrates that pathological evidence of GVHD does not absolutely require the presence of genetic differences between host and donor and questions existing concepts about the nature of cyclosporine-induced GVHD.


Subject(s)
Bone Marrow Transplantation/immunology , Graft vs Host Disease/chemically induced , Intestinal Diseases/immunology , Acute Disease , Cyclosporine/adverse effects , Humans , Immunosuppressive Agents/adverse effects , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Transplantation, Isogeneic
17.
DNA Cell Biol ; 16(6): 671-8, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9212161

ABSTRACT

We have identified a putative transcription factor, designated hLim-1, from human fetal brain using degenerate polymerase chain reaction (PCR) and cDNA library screening. The deduced open reading frame, derived from sequencing a 3.0-kb hLim-1 cDNA, encodes a protein of 384 amino acids with two cysteine-rich LIM domains and one homeobox (HOX) DNA-binding domain. The nucleotide sequence of hLim-1 cDNA is 87% identical to mouse Lim-1 and the predicted amino acid sequence is greater than 97% conserved. Expression patterns of hLim-1 were evaluated by Northern analysis and reverse transcription (RT)-PCR coupled with Southern blotting. HLim-1 expression was observed in human brain, thymus, and tonsillar tissue. Expression of hLim-1 was also observed in 58% of acute myelogenous leukemia (AML) cell lines and in four of five primary samples from patients with chronic myeloid leukemia (CML) in myeloid blast transformation. The gene encoding hLim-1 was mapped using fluorescence in situ hybridization (FISH) to human chromosome 11p12-13. The expression pattern and structural characteristics of the hLim-1 gene suggest that it encodes a transcriptional regulatory protein involved in the control of differentiation and development of neural and lymphoid cells. Its expression in CML in blast crisis suggests that it may be involved with progression in this disease; a prospective study is required to confirm this.


Subject(s)
Chromosomes, Human, Pair 11 , Homeodomain Proteins/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , Cloning, Molecular , DNA, Complementary , Humans , In Situ Hybridization, Fluorescence , LIM-Homeodomain Proteins , Mice , Molecular Sequence Data , Sequence Homology, Amino Acid , Transcription Factors
18.
Proc Natl Acad Sci U S A ; 94(11): 5877-81, 1997 May 27.
Article in English | MEDLINE | ID: mdl-9159168

ABSTRACT

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries, and there is significant variability in survival within CLL clinical stages. Earlier studies showed that CLL cells produce and are usually growth inhibited by transforming growth factor beta type 1 (TGF-beta1), suggesting a mechanism for the clinically indolent course of most CLL. Here we studied the mechanism by which CLL cells from about one-third of the patients are insensitive to TGF-beta1. Of the 13 patients studied, CLL cells isolated from the peripheral blood of 8 patients were sensitive to growth inhibition by TGF-beta1, as determined by incorporation of tritiated thymidine, whereas those from 5 patients were completely resistant to TGF-beta1. As judged by binding of radiolabeled TGF-beta1 followed by cross-linking and immunoprecipitation with anti-receptor antisera, CLL cells sensitive to TGF-beta1 exhibited normal cell surface expression of both types 1 and 2 TGF-beta receptors. In contrast, all CLL cells resistant to TGF-beta1 exhibited no detectable surface type I receptors able to bind TGF-beta1, but normal expression of type II receptors. Both TGF-beta1-sensitive and TGF-beta1-resistant CLL cells contained normal amounts of both type 1 and type 2 receptor mRNAs. Specific loss of type 1 receptor expression represents a new mechanism by which cells acquire resistance to TGF-beta1-mediated growth inhibition in the development and progression of human lymphoproliferative malignancies.


Subject(s)
Activin Receptors, Type I , Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology , Lymphocytes/immunology , Receptors, Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/pharmacology , Adult , Antigens, CD/biosynthesis , Antigens, CD/blood , Cell Division , Cell Membrane/immunology , DNA, Neoplasm/biosynthesis , Humans , Immunophenotyping , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphocyte Activation/drug effects , Lymphocytes/drug effects , Neoplasm Staging , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/physiology , Receptor, Transforming Growth Factor-beta Type I , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/physiology , Thymidine/metabolism , Transcription, Genetic , Tumor Cells, Cultured
19.
Blood ; 89(7): 2276-82, 1997 Apr 01.
Article in English | MEDLINE | ID: mdl-9116269

ABSTRACT

Mutations in the DNA mismatch repair (MMR) gene hMSH2 underlie a novel pathway of tumorigenesis for some cancers of epithelial origin. Mice deficient in MSH2 are susceptible to lymphomas but defects in this gene have not been identified in human lymphoid tumors. To determine if the lymphomas these mice develop are related to a particular subtype of human lymphoma we evaluated 20 clinically ill homozygous MSH2-/- mice ranging in age from 2 to 13 months. The murine tumors comprised a single histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembled human precursor T-cell lymphoblastic lymphoma (LBL). Evaluation of the expression of three T-cell malignancy associated genes showed that Rhombotin-2 (RBTN-2 also known as Lmo-2), TAL-1 (also known as SCL), and HOX-11 were expressed in 100%, 40%, and 0% of the murine tumors, respectively. The MSH2-/- murine model of precursor T-cell LBL was substantiated by the finding of a nearly identical expression profile of RBTN-2, TAL-1, and HOX-11 in 10 well-characterized cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was established by sequence analysis of exon 13 of hMSH2, which revealed coding region mutations in 2 of 10 cases. Our findings implicate defects in the MMR system with the aberrant expression of T-cell specific proto-oncogenes and define a new pathway of human lymphomagenesis.


Subject(s)
DNA Repair/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/physiology , Fungal Proteins , Gene Expression Regulation, Neoplastic , Metalloproteins/biosynthesis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins , Transcription Factors , Adaptor Proteins, Signal Transducing , Animals , Basic Helix-Loop-Helix Transcription Factors , DNA-Binding Proteins/genetics , Exons/genetics , Homeodomain Proteins/biosynthesis , Homeodomain Proteins/genetics , Humans , LIM Domain Proteins , Metalloproteins/genetics , Mice , Mice, Knockout , Molecular Sequence Data , MutS Homolog 2 Protein , Oncogene Proteins/biosynthesis , Oncogene Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogenes , T-Cell Acute Lymphocytic Leukemia Protein 1
20.
Br J Haematol ; 93(1): 163-5, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8611454

ABSTRACT

The recurrence of leukaemia following allogeneic bone marrow transplantation appears to develop rarely in donor cells. However, the standard method for assigning the origin of recurrence, metaphase analysis, can be unreliable. We have applied the technique of fluorescence in situ hybridization (FISH) directly on archival Wright stained bone marrow slides obtained from a patient who developed acute myelogenous leukaemia (AML) following allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia (CML). Using a chromosome-specific DNA probe we linked a chromosomal aberration, previously detected by conventional metaphase analysis, directly to morphologically identifiable blast cells. In this way we were able to assess cell-lineage involvement of the secondary leukaemia and assign a donor origin.


Subject(s)
Bone Marrow Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukemia, Myeloid, Acute/complications , Tissue Donors , Adult , Cell Lineage , Chromosome Deletion , Chromosomes, Human, Pair 7 , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Transplantation, Homologous
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