Immunotherapy of established tumors using bone marrow transplantation with antigen gene–modified hematopoietic stem cells

10.1038/nm882 ◽  
2003 ◽  
Vol 9 (7) ◽  
pp. 952-958 ◽  
Author(s):  
Yan Cui ◽  
Erin Kelleher ◽  
Erin Straley ◽  
Ephraim Fuchs ◽  
Kevin Gorski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cells ◽  
Marrow Transplantation ◽  
Hematopoietic Stem ◽  
Antigen Gene

Role Of Sf3b1 On Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 600-600
Author(s):  
Manabu Matsunawa ◽  
Ryo Yamamoto ◽  
Masashi Sanada ◽  
Aiko Sato ◽  
Yusuke Shiozawa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cells ◽  
Marrow Transplantation ◽  
Bone Marrow Cells ◽  
Hematopoietic Stem ◽  
Ring Sideroblasts ◽  
Marrow Cells

Abstract Frequent pathway mutation involving multiple components of the RNA splicing machinery is a cardinal feature of myeloid neoplasms showing myeloid dysplasia, in which the major mutational targets include U2AF35, ZRSR2, SRSF2 and SF3B1. Among these, SF3B1 mutations were strongly associated with MDS subtypes characterized by increased ring sideroblasts, such as refractory anemia and refractory cytopenia with multiple lineage dysplasia with ring sideroblasts, suggesting the critical role of SF3B1 mutations in these MDS subtypes. However, currently, the molecular mechanism of SF3B1mutation leading to the ring sideroblasts formation and MDS remains unknown. The SF3B1 is a core component of the U2-small nuclear ribonucleoprotein (U2 snRNP), which recognizes the 3′ splice site at intron–exon junctions. It was demonstrated that Sf3b1 null mice were shown to be embryonic lethal, while Sf3b1 +/- mice exhibited various skeletal alterations that could be attributed to deregulation of Hox gene expression due to haploinsufficiency of Sf3b1. However, no detailed analysis of the functional role of Sf3b1 in hematopoietic system in these mice has been performed. So, to clarify the role of SF3B1 in hematopoiesis, we investigated the hematological phenotype of Sf3b1 +/- mice. There was no significant difference in peripheral blood counts, peripheral blood lineage distribution, bone marrow total cellularity or bone marrow lineage composition between Sf3b1 +/+ and Sf3b1 +/- mice. Morphologic abnormalities of bone marrow and increased ring sideroblasts were not observed. However, quantitative analysis of bone marrow cells from Sf3b1 +/- mice revealed a reduction of the number of hematopoietic stem cells (CD34 neg/low, cKit positive, Sca-1 positive, lineage-marker negative: CD34-KSL cells) measured by flow cytometry analysis, compared to Sf3b1 +/+ mice. Whereas examination of hematopoietic progenitor cells revealed a small decrease in KSL cell populations and megakaryocyte - erythroid progenitors (MEP) in Sf3b1 +/- mice, and common myeloid progenitors (CMP), granulocyte - monocyte progenitors (GMP) and common lymphoid progenitors (CLP) remained unchanged between Sf3b1 +/+ and Sf3b1 +/- mice. In accordance with the reduced number of hematopoietic stem cells in Sf3b1 +/- mice, the total number of colony-forming unit generated from equal number of whole bone marrow cells showed lower colony number in Sf3b1 +/- mice in vitro. Competitive whole bone marrow transplantation assay, which irradiated recipient mice were transplanted with donor whole bone marrow cells from Sf3b1 +/+ or Sf3b1 +/- mice with an equal number of competitor bone marrow cells, revealed impaired competitive whole bone marrow reconstitution capacity of Sf3b1 +/- mice in vivo. These data demonstrated Sf3b1 was required for hematopoietic stem cells maintenance. To further examine the function of hematopoietic stem cells in Sf3b1 +/- mice, we performed competitive transplantation of purified hematopoietic stem cells from Sf3b1 +/+ or Sf3b1 +/- mice into lethally irradiated mice together with competitor bone marrow cells. Sf3b1 +/- progenitors showed reduced hematopoietic stem cells reconstitution capacity compared to those from Sf3b1 +/+ mice. In serial transplantation experiments, progenitors from Sf3b1 +/- mice showed reduced repopulation ability in the primary bone marrow transplantation, which was even more pronounced after the second bone marrow transplantation. Taken together, these data demonstrate that Sf3b1 plays an important role in normal hematopoiesis by maintaining hematopoietic stem cell pool size and regulating hematopoietic stem cell function. To determine the molecular mechanism underlying the observed defect in hematopoietic stem cells of Sf3b1 +/- mice, we performed RNA-seq analysis. We will present the results of our biological assay and discuss the relation of Sf3b1 and hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals G-CSF-Primed Bone Marrow As a Source of Hematopoietic Stem Cells for Allogeneic Transplantation in Malignant and Non-Malignant Hematological Disorders

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2481-2481
Author(s):  
Eucario León-Rodríguez ◽  
Patricia Guzmán-Uribe ◽  
Marcela Deffis Court ◽  
Sandra Ileana Perez-Alvarez ◽  
Monica M Rivera Franco
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cells ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Hematopoietic Stem ◽  
Hematological Disorders

Abstract Introduction: To date, worldwide, the main source of stem cells is peripheral blood (PBSCs). However, its use has been associated with a higher incidence of graft versus host disease (GVHD) when compared with the use of bone marrow. It has been demonstrated that the fast engraftment using G-CSF-primed bone marrow as a source of stem cells, compares to that seen with PBSCs, and it is also associated with a decreased incidence of GVHD. Objective: To describe the results obtained from allogeneic, G-CSF-primed bone marrow transplantations, at INCMNSZ, from November 1998 to March 2013. Material and methods: A retrospective analysis was performed in patients who underwent allogeneic, G-CSF-primed bone marrow transplantation. Clinical characteristics, frequency of GVHD, and survival, were conducted, using the Statistical Software Package SPSS v21.0. Results: Forty-nine patients who underwent allogeneic, G-CSF-primed bone marrow transplantation, from November 1998 to March 2013, were included. Patients (male, 63%) had a median age of 29 years (range 16-59). The patients had a following range of underlying diseases: aplastic anemia (n=15, 30.6%), myelodysplastic syndrome (n=12, 24.5%), chronic myeloid leukemia (CML, n=9, 18.4%), acute lymphoblastic leukemia (LLA, n=7, 14.3%), acute myeloid leukemia (AML, n=3, 6.1%), or others (n=3, 6.1%). Patients achieved a bilineage engraftment with a median time of 20 days (range, 11-40) for absolute neutrophil count and 15 days (range, 5-45) for platelets. Acute GVHD was observed in 4 patients (8.2%), reported as grade I and II; and 14 patients (28.6%) experienced a limited form of chronic GVHD. Nine out of 49 (18.3%) patients relapsed: CML (n=5), AML (n=1), AA (n=1), ALL (n=1), others (n=1). All patients with relapsed CML were treated with donor lymphocyte infusions, but only 2 responded. Treatment related mortality (TRM) was 8.16%, including infectious complications in 2 patients, cGVHD in one patient, and veno-oclussive disease (VOD) in one patient. Overall mortality was 26.5%; the majority of deaths (69.2%) were caused by progressive and relapsing disease. With a follow up of 43 months (0-149), the median overall survival (OS) has not been reached; however, the estimated 10-year OS is 69%. Conclusion: According to our data, it seems that G-CSF-primed bone marrow is a better source of hematopoietic stem cells for allogeneic transplantation in malignant and non-malignant hematological disorders, when compared with PBSCs, due to the similar engraftment time, and a decreased incidence and severity of acute and chronic GVHD. Nevertheless, this strategy does not appear to be valid as an approach for diseases were graft versus tumor effect (GVT) is important to eradicate the malignancy, such as in CML. Disclosures No relevant conflicts of interest to declare.

Method — Intra-bone marrow transplantation of hematopoietic stem cells in non-human primates: long-term engraftment without conditioning

2004 ◽  
Vol 2 (3) ◽  
pp. 207-218
Author(s):  
Kyoji Ueda ◽  
Yutaka Hanazono ◽  
Naohide Ageyama ◽  
Hiroaki Shibata ◽  
Satoko Ogata ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Hematopoietic Stem Cells ◽  
Marrow Transplantation ◽  
Hematopoietic Stem
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