| 1. |
- Aguilo, Francesca, et al.
(författare)
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Prdm16 is a physiologic regulator of hematopoietic stem cells.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 117:19
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Tidskriftsartikel (refereegranskat)abstract
- Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.
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| 2. |
- Armstrong, Scott A, et al.
(författare)
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FLT3 mutations in childhood acute lymphoblastic leukemia.
- 2004
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 103:9, s. 3544-3546
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of the FLT3 receptor tyrosine kinase are common in acute myelogenous leukemia (AML) but are rare in adult acute lymphoblastic leukemia (ALL). We have recently shown that FLT3 is highly expressed and often mutated in ALLs with rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Because hyperdiploid ALL samples also show high-level expression of FLT3, we searched for the presence of FLT3 mutations in leukemic blasts from 71 patients with ALL. The data show that approximately 25% (6 of 25) of hyperdiploid ALL samples possess FLT3 mutations, whereas only 1 of 29 TEL/AML1-rearranged samples harbored mutations (P =.04, Fisher exact test). Three mutations are novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. Finally, 3 samples from patients whose disease would relapse harbored FLT3 mutations. These data suggest that patients with hyperdiploid or relapsed ALL might be considered candidates for therapy with newly described small-molecule FLT3 inhibitors.
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| 3. |
- Avagyan, Serine, et al.
(författare)
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Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:23
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.
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| 4. |
- Balgobind, Brian V, et al.
(författare)
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Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia : results of an international retrospective study.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 114:12, s. 2489-2496
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Tidskriftsartikel (refereegranskat)abstract
- Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.
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| 5. |
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| 6. |
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| 7. |
- Bruce, Lesley J, et al.
(författare)
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Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man : an interaction between the Rh complex and the band 3 complex.
- 2002
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 100:5, s. 1878-1885
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Tidskriftsartikel (refereegranskat)abstract
- We present data on a patient of South Asian origin with recessive hereditary spherocytosis (HS) due to absence of protein 4.2 [4.2 (-) HS]. Protein 4.2 cDNA sequence analysis showed the presence of a novel 41-bp frameshift deletion that predicts a truncated peptide designated protein 4.2 Hammersmith. Quantitative reverse transcription-polymerase chain reaction indicated that the mutant mRNA was unstable. Sequencing of protein 4.2 genomic DNA revealed that the deletion stems from aberrant splicing. The proband was homozygous for a G>T substitution at position 1747 (cDNA numbering) that activates a cryptic acceptor splice site within exon 11 of the protein 4.2 gene (EPB42). The proband's mother was found to be heterozygous for this substitution. Unlike protein 4.2 null mice, the proband's red cells showed no evidence for abnormal cation permeability. Quantitation of red cell membrane proteins was carried out by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting, and flow cytometric measurement. CD47, a protein associated with the Rh complex, was markedly reduced to about 1% (in the proband) and 65% (in the mother) that found in healthy controls. The Rh-associated glycoprotein migrated with a higher than normal apparent molecular weight on SDS-PAGE. There was no obvious reduction in Rh polypeptides. These observations indicate that protein 4.2 and CD47 interact in the human red cell membrane. They provide further evidence for an association between the band 3 complex (band 3, ankyrin, protein 4.2, glycophorin A) and the Rh complex (Rh-associated glycoprotein, Rh polypeptides, glycophorin B, CD47, LW) and define a point of attachment between the Rh complex and the red cell cytoskeleton.
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| 8. |
- Buitenkamp, Trudy D., et al.
(författare)
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Acute lymphoblastic leukemia in children with Down syndrome : a retrospective analysis from the Ponte di Legno study group
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 123:1, s. 70-77
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Tidskriftsartikel (refereegranskat)abstract
- Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
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| 9. |
- Christensen, Sarah Friis, et al.
(författare)
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Labor Market Attachment in Patients with Myeloproliferative Neoplasms: A Nationwide Matched Cohort Study
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 138:Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Myeloproliferative neoplasms (MPNs) are characterized by a substantial symptom burden, risk of debilitating complications (e.g., thrombosis), and increased comorbidity. Recently, three comprehensive questionnaire studies (Mesa 2016, Harrison 2017, Jingbo 2018) have reported a high impact of MPNs on patients' ability to work. However, no registry-based studies have assessed labor market attachment (LMA) of MPN patients and matched nonMPN comparisons.AIM: To assess the pre- and post-diagnostic LMA of MPN patients and matched nonMPN comparisons.METHODS: We conducted a descriptive, registry-based nationwide cohort study, using data from the Danish National Chronic Myeloid Neoplasia Registry including all Danish MPN patients diagnosed between January 2010 and December 2016. Population-based cohorts of nonMPN comparisons were constructed by 1:10 matching on age, sex, level of education, and region of residence. Data on LMA were retrieved from the Danish Register for Evaluation of Marginalization, which holds information on all public transfer payments in Denmark. Data were linked using the unique civil registration number, which identifies all Danish citizens. The LMA endpoints were defined for each individual as working (not receiving any type of transfer payment), unemployed, receiving transfer payment for either sick leave, disability pension, age pension, or other health-related benefits (e.g., wage-subsidized employment). We assessed LMA weekly for each individual from two years before diagnosis until death, emigration, or two years after the diagnosis. For each cohort, we presented LMA as proportions with 95% confidence intervals (CIs), as well as the proportion of individuals who died during follow-up.RESULTS: The study included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 myelofibrosis [MF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age at time of diagnosis was: ET 67 years (interquartile range [IQR], 55-76); PV, 69 years (IQR, 61-77); PMF, 73 years (IQR, 66-79); and MPN-U, 72 years (IQR, 63-80).At time of MPN diagnosis, the majority of MPN patients and nonMPN comparisons received age pension (range: ET, 52.1% [95% CI, 49.2-55.0] to nonMF, 70.3% [95% CI, 69.1-71.6]). The proportions working were: ET, 35.1% (95% CI, 32.3-37.9) vs. nonET, 37.3% (95% CI, 36.5-38.2); PV, 22.6% (95% CI, 20.2-25.1) vs. nonPV, 30.8% (95% CI, 29.9-31.7); MF, 23.8% (95% CI, 20.2-27.4) vs. nonMF, 23.6% (95% CI, 22.5-24.8); and MPN-U, 22.1% (95% CI,18.7- 25.6) vs. nonMPN-U, 27.8% (95% CI, 26.6-29.0). Across MPN subtypes, a larger proportion of patients than comparisons were on sick leave: ET, 3.5% (95% CI, 2.4-4.6) vs. nonET, 1.3% (95% CI, 1.1-1.5); PV, 5.5% (95% CI, 4.2-6.8) vs. nonPV, 0.9% (95% CI, 0.7-1.1); MF (not applicable due to small numbers) vs. nonMF, 0.6% (95% CI, 0.4-0.8); and MPN-U, 3.0% (95% CI, 1.6- 4.5) vs. nonMPN-U, 1.0% (95% CI, 0.7-1.3). Regarding disability pension, the proportions ranged from 4.1% (95% CI, 2.4-5.8) to 5.0% (95% CI, 3.7-6.3) among patients and from 3.1% (95% CI, 2.6-3.6) to 4.7% (95% CI, 4.3-5.1) among comparisons. For both MPN patients and nonMPN comparisons, few were unemployed (≤3.3%) or received other health-related benefits (≤1.6%).Two years preceding diagnosis, the proportion of PV and MPN-U patients working was slightly lower than the matched comparisons: PV, 31.0% (95% CI, 28.4-33.8) vs. nonPV, 34.3% (95% CI, 33.5-35.2) and MPN-U, 28.2% (95% CI, 24.6-32.1) vs. nonMPN-U, 32.0% (95% CI, 30.7-33.2), while this difference was not observed between ET and MF patients and their respective comparisons.From two years before to two years after diagnosis, we observed slightly larger reductions in the proportion working among MPN patients than among comparisons. Among MPN patients, the proportion on sick leave including other health-related benefits, increased during the study period, while it remained unchanged among comparisons. The proportion of patients and comparisons on disability pension remained stable.CONCLUSION: Overall, our findings showed that Danish patients with ET, PV, MF, and MPN-U had slightly impaired LMA already two years before diagnosis and up to two years after diagnosis. Thus, fewer patients were working and more patients transferred to sick leave compared with matched individuals without MPN.
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| 10. |
- Coenen, Eva A, et al.
(författare)
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Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients : results of an international study
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 117:26, s. 7102-7111
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Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.
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