| 1. |
- Cederleuf, Henrik, et al.
(författare)
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Outcome of peripheral T-cell lymphoma in first complete remission : a Danish-Swedish population-based study
- 2017
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 58:12, s. 2815-2823
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we investigate the outcome of 109 Danish and 123 Swedish patients with nodal PTCL in first complete remission (CR), and examine the impact of imaging-based follow-up (FU) strategies. The patients were selected by the following criteria: (a) newly diagnosed nodal PTCL from 2007 to 2012, (b) age ≥18 years, and (c) CR after CHOP or CHOEP therapy. FU guidelines in Sweden included symptom assessment, clinical examinations and blood tests at 3–4-month intervals for 2 years. FU strategies in Denmark was similar but included routine imaging, usually every 6 months for 2 years. Patients had fully comparable characteristics. Overall survival (OS) estimates for patients in CR were similar for all patients (p =.6) and in PTCL subtypes. In multivariate analysis, country of follow-up had no impact on OS. However, despite continuous CR for ≥2 years, the OS of PTCL remained inferior to a matched general population.
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| 2. |
- Cederleuf, Henrik, et al.
(författare)
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The addition of etoposide to CHOP is associated with improved outcome in ALK+ adult anaplastic large cell lymphoma : A Nordic Lymphoma Group study
- 2017
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 178:5, s. 739-746
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic large cell lymphomas (ALCLs) are rare CD30+ peripheral T-cell lymphomas (PTCLs) classified according to the expression of the anaplastic lymphoma kinase (ALK+) protein or not (ALK-). We have analysed the outcome and risk factors for survival in a population-based bi-national cohort of patients with systemic ALK+ ALCL. A total of 122 adult (≥18 years) patients diagnosed with ALK+ ALCL between 2000 and 2010 were identified from the Danish and Swedish lymphoma registries, representing 0·4% of all lymphomas. The median age of the cohort was 40 years (range 18-85). The 5-year overall survival and progression-free survival (PFS) was 78% and 64%, respectively. Age was strongly associated with outcome, and only bone marrow (BM) involvement was independently associated with poorer PFS in multivariate analysis (Hazard Ratio [HR] = 8·57, P < 0·001). Age stratification of the patients demonstrated an association between treatment with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) and improved overall survival for patients aged 41-65 years, even when adjusted for risk factors (HR = 0·38, P = 0·047). Our results suggest that the addition of etoposide to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) in the treatment for ALK+ ALCL seems reasonable in this age group.
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| 3. |
- Ellin, Fredrik, et al.
(författare)
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Central nervous system relapse in peripheral T-cell lymphomas: A Swedish lymphoma registry study.
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 126:1, s. 36-41
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Tidskriftsartikel (refereegranskat)abstract
- Central Nervous System (CNS) relapse in non-Hodgkin lymphomas (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, and the outcome of these patients, in a large population-based cohort of PTCL patients. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis disease characteristics at diagnosis independently associated with an increased risk of later CNS involvement were involvement of >1 extranodal site (Hazard Ratio [HR] 2.60, 95% Confidence Interval [95% CI] 1.07-6.29, p=0.035), skin (HR 3.51, 95% CI 1.26-9.74, p=0.016) and gastrointestinal involvement (HR 3.06, 95% CI 1.30-7.18, p=0.010). The outcome of relapsed/refractory patients was very poor and CNS involvement was not associated with a significantly worse outcome compared to relapsed/refractory patients without CNS involvement in multivariable analysis (HR 1.6, 95% CI 0.96-2.6, p=0.074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease.
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| 4. |
- Ellin, Fredrik
(författare)
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Clinical factors and outcome in T-cell lymphoma: a population-based perspective
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The heterogeneous group of T-cell lymphomas consist mostly of aggressive diseasess, with generally unfavourable outcome compared to aggressive B-cell lymphomas following similar therapy. This thesis focus on outcome and risk factors for inferior survival, in an unselected population-based cohort of T-cell lymphoma patients. In the first study, outcome of the precursor malignancy T-cell Lymphoblastic Lymphoma was investigated. This lymphoma has many similarities to T-cell Acute Lymphoblastic Leukemia, and intensive chemotherpay developed for leukemia is known to result in better outcome, than standard lymphoma therapies. The study confirms the superior survival after intensive therapy also in a population-based setting. Intensive as opposed to non-intensive treatment was the main prognostic factor for survival, while age was not associated with an inferior outcome among intensively treated patients. The other three studies focus on outcome in peripheral T-cell lymphomas (PTCL). The second study investigates outcome according to treatment and standard clinical factors at diagnosis. Male gender was found to be associated with inferior survival. Intensification of first-line treatment with up-front autologous stem cell transplantation (auto SCT) consolidation was found to be associated with a favourable outcome in patients younger than 70 years. Relapsing patients had a dismal outcome, with a median post relapse survival of 6 months. Study number three focused on the occurance of central nervous system (CNS) relapse in PTCL. In all, 28 patients (4.5%) experienced CNS relapse, most commonly with leptomeningeal involvement. Extensive extranodal involvement, skin or gastrointestinal involvement was associated with a higher risk for secondary CNS spread. At relapse patients had a very poor survival, irrespective of CNS involvement or not, with no survival difference between the groups. The last study investigates the impact of comorbidity in PTCL. Using the Charlson Comorbidity Index (CCI), presence of concomittant disease was found to be independently associated with inferior survival. CCI was the only factor at diagnosis that showed an association with survival after first-line auto SCT. The association with favourable outcome in patients treated with auto SCT found in the second study, was still significant when adjusting for CCI. In patients ≥75 years, a similar survival in patients treated with curative and low-intensity chemotherapy was found. This was not changed when adjusting for the CCI. In summary, the studies included in this thesis provides information on risk factors and population-based outcomes in T-cell lymphomas. Associations between treatment intensification and better outcome suggests a beneficial effect of these strategies in younger patients. The thesis also provides information on previously poorly documented disease, and patient-related, factors in PTCL, and will possibly serve as comparative data for future population-based studies.
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| 5. |
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| 6. |
- Ellin, Fredrik, et al.
(författare)
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Impact of comorbidity on survival in peripheral T-cell lymphomas : A Swedish Lymphoma Registry study
- 2018
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Ingår i: Hematological Oncology. - : Wiley. - 0278-0232. ; 36:1, s. 159-165
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Tidskriftsartikel (refereegranskat)abstract
- Comorbidity impacts survival in B-cell lymphoma patients, but the influence in peripheral T-cell lymphomas (PTCLs) has been little studied. To investigate the impact of comorbidity on outcome in PTCL, we identified adult patients with newly diagnosed PTCL from 2000 to 2009 in the Swedish Lymphoma Registry. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI). Comorbid conditions were present in 263 out of 694 (38%) patients. A CCI score of ≥2 was associated with inferior overall survival (OS) (hazard ratio [HR] 1.63, P < .001) and progression-free survival (HR 1.54, P < .001) in multivariate analysis. In patients undergoing front-line autologous stem cell transplantation (auto SCT), CCI >0 was associated with inferior OS (HR 2.40, P = .013). Chemotherapy regimens were classified as curative or low-intensity treatments. Among patients aged ≥75 years (n = 214), low-intensity and curative treatment groups had similar OS (HR 0.8, P = .6), also when adjusted for CCI. In summary, our results demonstrate CCI to be independently associated with survival in PTCLs. Even limited comorbidity impacted survival after front-line auto SCT, which needs to be considered in treatment decisions. Intensive anthracycline-based chemotherapy in elderly PTCL patients might be of limited benefit.
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| 7. |
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| 8. |
- Ellin, Fredrik, et al.
(författare)
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Real world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry.
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 124:10, s. 1570-1577
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral T-cell Lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. Addition of etoposide to CHOP and up-front consolidation with autologous stem cell transplantation (autoSCT) have shown promising results, but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index (IPI) factors, male gender was associated with an adverse overall survival (OS) (HR 1.28, p=0.011) and progression-free survival (PFS) (HR 1.26, p=0.014). In an intention-to-treat analysis in 252 nodal PTCL and EATL patients (excluding ALK-positive ALCL), up-front autoSCT was associated with a superior OS (HR 0.58, p=0.004) and PFS (HR 0.56, p=0.002) compared to patients treated without autoSCT. Addition of etoposide to CHOP resulted in superior PFS in patients up to 60 years (HR 0.49, p=0.008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials.
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| 9. |
- Ellin, Fredrik, et al.
(författare)
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Treatment outcome in T-cell lymphoblastic lymphoma in adults : a population-based study from the Swedish Lymphoma Registry
- 2014
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 53:7, s. 927-934
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Tidskriftsartikel (refereegranskat)abstract
- Background. T-cell lymphoblastic lymphoma (T-LBL) is a rare neoplasm of precursor lymphoblast origin, for which there is no standard treatment for adults. Results of current treatment strategies in selected populations do exist but are largely unreported for unselected series. Here, we aimed to investigate treatment outcome in a population-based cohort. Material and methods. Patients were identified through the Swedish Lymphoma Registry and data was retrospectively collected for all adult (>= 18 years) Swedish T-LBL patients diagnosed during 2000-2009. Results. A total of 39 patients with median age 40 years (range 18-78) were identified with females being significantly older than males (median age 66 vs. 37, p = 0.027). The five-year overall survival for all patients was 42%. Female gender was associated with shorter survival also when adjusted for treatment strategy and age [hazard ratio (HR) 4.29; p = 0.002]. Thirty patients received intensive chemotherapy, otherwise used for treatment of acute lymphoblastic leukemia (ALL), which resulted in an overall response rate of 97% and a five-year progression-free survival (PFS) of 49%. In this group only CNS involvement at diagnosis predicted shorter PFS (HR 13.3; p = 0.03). Among patients treated with hyper-CVAD the addition of mediastinal irradiation resulted in prolonged time to progression compared to patients receiving only chemotherapy (p = 0.047). The major reason for treatment failure was relapse and in this series 18-fluoro-deoxyglucose positron emission tomography (PET) did not predict this risk. Conclusion. This population-based study indicates that all fit T-LBL patients should be considered for intensive treatment. Our results also suggest a beneficial effect of mediastinal irradiation in combination with hyper-CVAD treatment. Relapsing patients have a dismal outcome irrespective of salvage treatment.
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| 10. |
- Jakobsen, Lasse H., et al.
(författare)
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Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy : an international study of 264 real-world patients
- 2020
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 189:4, s. 661-671
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Tidskriftsartikel (refereegranskat)abstract
- Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.
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| 11. |
- Jerkeman, Mats, et al.
(författare)
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Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma : The Swedish MCLcomplete Project
- 2023
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Ingår i: HemaSphere. - : Ovid Technologies (Wolters Kluwer Health). - 2572-9241. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006-2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL.
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| 12. |
- Mattsson, Agnes, et al.
(författare)
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Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia : A Swedish nation-wide real-world report on consecutively identified patients
- 2023
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 111:5, s. 715-721
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesWe examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL).Methods and ResultsThirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1–11); the median age was 69 years (range 50–89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9–44.8). The median progression-free survival was 16.4 months (95% CI: 10.4–26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%).ConclusionsOur real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.
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| 13. |
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| 14. |
- Maurer, Matthew J., et al.
(författare)
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International Assessment of Event-Free Survival at 24 Months and Subsequent Survival in Peripheral T-Cell Lymphoma
- 2017
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 35:36, s. 4019-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.
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| 15. |
- Mead, Monica, et al.
(författare)
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Impact of comorbidity in older patients with peripheral T-cell lymphoma : an international retrospective analysis of 891 patients
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:7, s. 2120-2128
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive neoplasms with poor outcomes, commonly affecting older patients with comorbidities. This study aims to describe outcomes of older patients with PTCL in a large international cohort. Patients aged $70 years with PTCL diagnosed from 1 January 2010 to 31 December 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. Data on comorbidity were retrospectively collected according to the Charlson Comorbidity Index (CCI), and clinical outcomes were extracted. A total of 891 patients were included (SLR, n 5 173; CCR, n 5 718). Median age was 77 (SLR) and 78 (CCR) years. Included subtypes were as follows: angioimmunoblastic T-cell lymphoma, n 5 226; anaplastic large-cell lymphoma, n 5 122; enteropathy-associated T-cell lymphoma (EATL), n 5 31; hepatosplenic TCL, n 5 7; natural killer–/T-cell lymphoma, n 5 62; PTCL not otherwise specified, n 5 443. CCI data were available in 775 patients (87%), and CCI scores were divided into the groups CCI 5 0 (39%), CCI 5 1 (22%), and CCI . 1 (39%). Median age did not differ among the CCI groups (P 5 .72). Patients with a CCI . 1 had a worse median overall survival (4.4 months) compared with patients with CCI 5 0 (11.9 months) and CCI 5 1 (8.4 months; P, .001). Comorbidity and advancing age in as little as 5-year increments are important adverse factors in this group. Most patients died of lymphoma within a year from diagnosis, underscoring the importance of developing new treatments.
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| 16. |
- Olszewski, Adam J., et al.
(författare)
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Burkitt Lymphoma International Prognostic Index
- 2021
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 39:10, s. 1129-1138
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.
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| 17. |
- Ringvall, Maria, et al.
(författare)
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Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1
- 2000
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 275:34, s. 25926-25930
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate is a sulfated polysaccharide present on most cell surfaces and in the extracellular matrix. In vivo functions of heparan sulfate can be studied in mouse strains lacking enzymes involved in the biosynthesis of heparan sulfate. Glucosaminyl N-deacetylase/N-suLfotransferase (NDST) catalyzes the first modifying step in the biosynthesis of the polysaccharide. This bifunctional enzyme occurs in several isoforms. We here report that targeted gene disruption of NDST-1 in the mouse results in a structural alteration of heparan sulfate in most basement membranes as revealed by immunohistochemical staining of fetal tissue sections using antibodies raised against heparan sulfate. Biochemical analysis of heparan sulfate purified from fibroblast cultures, lung, and liver of NDST-1-deficient embryos demonstrated a dramatic reduction in N-sulfate content. Most NDST-1-deficient embryos survive until birth; however, they turn out to be cyanotic and die neonatally in a condition resembling respiratory distress syndrome. In addition, a minor proportion of NDST-1 deficient embryos die during the embryonic period. The cause of the embryonic lethality is still obscure, but incompletely penetrant defects of the skull and the eyes have been observed.
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| 18. |
- Schéele, Susanne, et al.
(författare)
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Laminin {alpha}1 globular domains 4-5 induce fetal development but are not vital for embryonic basement membrane assembly.
- 2005
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:5, s. 1502-1506
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Tidskriftsartikel (refereegranskat)abstract
- basement membrane (BM) assembly, which is required for pregastrulation development. Individual domains may have other functions, not necessarily structural. The cell binding C terminus of Lm {alpha}1 chain contains five Lm globular (LG) domains. In vitro, {alpha}1LG1–3 domains bind integrins, and {alpha}1LG4 binds dystroglycan, heparin, and sulfatides. A prevailing hypothesis is that {alpha}1LG4 is crucial as a structural domain for BM assembly, whereas integrin-binding sites conduct signaling. The in vivo role of {alpha}1LG4–5 (also called E3) has not been studied. Mice lacking {alpha}1LG4–5 were therefore made. Null embryos implanted, but presumptive epiblast cells failed to polarize and did not survive past day 6.5. BM components including truncated Lm {alpha}1 were detected in Reichert's membrane. Surprisingly, embryonic BM assembly between visceral endoderm and stem cells was normal in null embryos and in embryoid bodies of {alpha}1LG4–5-null embryonic stem cells. Yet, stem cells could not develop into polarized epiblast cells. Thus, {alpha}1LG4–5 provides vital signals for the conversion of stem cells to polarized epithelium.
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