T Cell Acute Lymphoblastic Leukemia Originates from a Differentiation Block in T Cell Development Due to Aberrant Expression of LMO2 and SCL(TAL1).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2215-2215
Author(s):  
Gerlinde Layh-Schmitt ◽  
Scott Crable ◽  
Kathleen Crable ◽  
Elizabeth Kraft ◽  
Jeff Bailey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Development ◽  
Aberrant Expression ◽  
Differentiation Block ◽  
Marrow Cells

Abstract T cell acute lymphoblastic leukemia (T-ALL) is frequently associated with overexpression of the oncogenes LMO2 and SCL(TAL1) which are normally down regulated following the double negative stage of T cell development. Our goal is to decipher the molecular and cellular mechanisms leading to the onset of LMO2 associated T-ALL. We were able to isolate a complex containing the transcription factors LMO2, SCL(TAL1) and E47 from primary human T-ALL cells with proven aberrant expression of LMO2 and SCL(TAL1) by applying immunoprecipitation and Western blotting techniques. This protein complex regulates the transcription of a truncated form of RALDH2 (retinaldehyde dehydrogenase) in T-ALL cells as shown by gene transcription profiling in conjunction with RT-PCR and siRNA approaches. To monitor the effect of LMO2 expression on T cell development and leukemogenesis, lethally irradiated mice (C57BL/6) were transplanted with bone marrow cells that had been transduced with a retrovirus carrying LMO2 as the transgene. One year later, 88% of the cells in the thymus expressed LMO2 and a shift towards CD3−/CD44+/CD25+ cells was observed (an 88% increase compared to normal thymocytes), suggesting a differentiation block caused by LMO2 leading to an accumulation of immature T cells. To test and identify cooperating genes in T-ALL development, bone marrow cells of LMO2 double transgenic mice in which tet-inducible LMO2 is controlled by a thymic specific promoter, were retrovirally transduced with SCL(TAL1). So far, none of the control animals, transplanted with bone marrow cells transduced with a vector only containing EGFP, developed T-ALL. However, six out of the seven test animals developed T-ALL exhibiting enlargement of the spleen, liver and thymus between seven and nine months after transplantation. Organs and blood of the diseased animals were infiltrated with T-ALL cells of the immature phenotype CD8+/CD4+ in five cases and of the CD3−/CD44+/CD25+ phenotype in one case. This indicates that the differentiation block caused by a lack of down-regulation of LMO2 and SCL(TAL1) in maturing T cells leads to a block in T cell differentiation and precedes T-ALL. These models will be used to examine the involvement of other cooperating genes in T-ALL development as well as downstream target genes of LMO2/SCL(TAL1), such as RALDH2, in the onset of T-ALL. We conclude that aberrant expression of LMO2 in T cells leads to a block in T cell maturation and, in conjunction with up-regulation of secondary genes like SCL(TAL1), triggers deregulation of genes in immature T cells leading to impaired T cell development and the onset of T-ALL. The described model will help to identify cooperating genes in LMO2 associated T-ALL as well as the chain of events leading to malignancy.

LMO2 and TAL1 Cooperate in a Model of Human T−Cell Leukemogenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 773-773
Author(s):  
James A. Kennedy ◽  
Frederic Barabe ◽  
John E. Dick
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Early Event ◽  
Aberrant Expression ◽  
Human T Cell ◽  
Differentiation Block ◽  
Population Doublings ◽  
T Cell Leukemogenesis ◽  
T Lymphopoiesis

Abstract T−cell acute lymphoblastic leukemia (T−ALL) is associated with the aberrant expression of a limited number of genes, including the basic helix−loop−helix transcription factor TAL1 (SCL) and the LIM−only domain gene LMO2, in the T−cell lineage. These proteins are thought to mediate their leukemogenic effects by interfering with the transcriptional programs that regulate differentiation during normal thymocyte development. The recent X−linked SCID gene therapy trial has highlighted a role for LMO2 overexpression as an early event in T−lineage leukemogenesis, as retroviral integration into the LMO2 locus was detected in multiple patients that went on to develop T−ALL. However, our understanding of the effects of aberrant LMO2 expression upon human T−lymphopoiesis is currently limited. In order to address this area, lineage−depleted human umbilical cord blood cells were transduced with a lentivirus encoding LMO2 or a control virus, then seeded upon OP9−DL1 stroma. As expected, control cells underwent a normal stage−specific program of T cell development concluding with the emergence of a population of CD4+CD8+CD3hi TCRαβ+ cells. Interestingly, LMO2−expressing cells exhibited a differentiation block at the double negative (DN: CD8−CD4−CD7+) stage of T−cell development. These LMO2−expressing DN cells had a growth advantage compared to control cells (23 population doublings over 75 days for LMO2 vs. 15 p.d. over 60 days for control) but were not immortalized as they stopped expanding after 75 days of co−culture. In the context of T−cell leukemogenesis, these findings suggest that as an initial hit, LMO2 overexpression can induce a blockage in differentiation, resulting in the generation of a proliferative pre−leukemic pool of DN cells. These cells could subsequently accumulate additional mutations leading to the eventual development of an overt leukemia. Given that TAL1 has been shown to accelerate the development of leukemia in LMO2 transgenic mice, and that these two genes are simultaneously overexpressed in a significant percentage of T−ALL cases, this oncogene was an ideal candidate for a second genetic hit. Thus, a retrovirus encoding TAL1 was utilized to infect the LMO2+ DN T−cell population. The expression of TAL1 in these cells significantly increased their proliferative capacity and greatly extended their lifespan, as greater than 60 population doublings occurred over 220 days of culture on stroma. Of note, TAL−1 overexpression appeared to release the LMO2−induced differentiation block at the DN stage, resulting in the emergence of a population of CD4+CD8+CD3− lymphoblasts. Taken together, these findings describe the first experimental model that studies the early stages of human T−cell leukemogenesis by starting with the physiologically relevant population of primitive primary human hematopoietic cells and analyzing the impact of sequential genetic hits upon T−lymphopoiesis. These data indicate that the aberrant expression of LMO2 contributes to leukemogenesis as an early event by generating a pre−leukemic pool of DN cells and that TAL−1 overexpression in this population acts a cooperating event that leads to the emergence of a highly proliferative, immortalized clone. Given that an experimentally induced leukemia model requires the demonstration of in vivo disease, studies assessing the leukemic potential of human cells co−expressing TAL1 and LMO2 are underway in a novel NOD/SCID system that supports human T cell development.

The Orphan Nuclear Receptor NR2F6 Is a Novel Negative Regulator of T-Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 915-915
Author(s):  
Christine V. Ichim ◽  
Dzana Dervovic ◽  
Juan Carlo Zuniga-Pflucker ◽  
Richard A. Wells
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Nuclear Receptor ◽  
Bone Marrow Cells ◽  
Orphan Nuclear Receptor ◽  
Over Expression ◽  
Competitive Disadvantage ◽  
Marrow Cells

Abstract Abstract 915 The orphan nuclear receptor NR2F6 is a mammalian homologue of the Drosophila seven-up gene that plays key roles in decisions of cell fate in neuroblast and retinal cells. We have previously described a novel role for NR2F6 in decisions of cell fate of mammalian haematopoietic cells of the myeloid cell lineage. We have shown that over-expression of NR2F6 in bone marrow cells impairs differentiation and extends the proliferative capacity of myeloid and early progenitor cells eventually leading to acute myeloid leukaemia (AML), while silencing of NR2F6 expression in AML cell lines causes terminal differentiation and apoptosis. A role of NR2F6 in lymphopoiesis has yet to be identified. Here we describe for the first time a role for NR2F6 in the specification of lymphoid cells. NR2F6 expression is heterogeneous throughout the haematopoietic hierarchy, with expression being highest in long-term repopulating HSCs and generally declining with the differentiation of progenitor cells. We report that over-expression of NR2F6 abrogates the developmental program necessary for T-cell lymphopoiesis. We assessed the effects of NR2F6 on lymphopoiesis in vivo by competitive bone marrow transplantation of NR2F6-IRES-GFP or GFP retrovirally transduced grafts (n=43). Competitive repopulation of lethally irradiated murine hosts with GFP transduced bone marrow cells resulted in successful engraftment and T-cell development, with GFP+ T-cells present in the thymus, and periphery at rates comparable to the percent marked cells in the original graft. However over-expression of NR2F6 placed developing T-cells at a dramatic competitive disadvantage. Six weeks post transplant the proportion of CD3+ cells derived from NR2F6 transduced bone marrow cells was greatly diminished relative to control (more than 10 fold), while at 12 weeks post-transplant we observed an abrogation of CD3+ cells derived from NR2F6 transduced T-cells (with the percentage of NR2F6 transduced CD3+ cells being comparable to staining with IgG control) in both the thymus and periphery. This stark competitive disadvantage was observed in all recipients of NR2F6 transduced grafts. We confirmed that this is not a phenomenon specific to the marker CD3 by analysing a portion of the animals for expression of CD4 and CD8, which again showed a lack of mature t-cells. In a second series of bone marrow transplants, cells transduced with NR2F6 or GFP were purified by fluorescence-activated cell sorting and grafts of 100% transduced cells were transferred by tail vein injection into lethally irradiated recipients. Animals transplanted with NR2F6 transduced bone marrow demonstrated a gross decrease in their thymic size and cellularity (∼10 fold decrease, n=17). Furthermore, the thymus of NR2F6 transduced animals contained a larger proportion of non-transduced, GFP negative residual haematopoietic cells than the vector control animals, corroborating the competitive disadvantage that NR2F6 transduced bone marrow cells face in the thymus. As observed in our previous experiments these animals demonstrated a gross reduction in the proportion of CD3+ cells in the thymus, spleen, lymph nodes and peripheral blood. To rule out the possibility that over-expression of NR2F6 is preventing the trafficking of progenitor cells to the thymus we differentiated NR2F6 or GFP transduced haematopoietic stem cells (lin-,c-kit+,sca-1+) into T-cells in vitro on OP9-DL1 cells. We observed a drastic reduction in the number of cells generated from NR2F6 transduced stem/progenitor cells (>50 fold at day 23), suggesting that expression of NR2F6 greatly impairs T-cell development. Mechanistically, others have shown that NR2F6 functions as a transcriptional repressor inhibiting the transactivating ability of genes such as Runx1. We conjecture that in lymphoid progenitors as well NR2F6 functions as a transcriptional repressor preventing the activation of pathways necessary for T-cell survival, proliferation and lymphopoiesis. Taken together, these data establish that the orphan nuclear receptor NR2F6 is a novel negative regulator of T-cell lymphopoiesis, and demonstrate that down-regulation of NR2F6 is important for the survival and proliferation of T-cell progenitors. Disclosures: No relevant conflicts of interest to declare.

A Lineage-Specific Requirement for YY1 Polycomb Group Protein Function in Early T Cell Development

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Anna Luiza Facchetti Vinhaes Assumpcao ◽  
Guoping Fu ◽  
Zhanping Lu ◽  
Ashley Kuehnl ◽  
Renren Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Notch Signaling ◽  
Cell Survival ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Polycomb Group ◽  
Polycomb Group Protein

T cell development originates from hematopoietic stem and progenitor cells in the bone marrow, which migrate to the thymus and obtain T cell identification. Transcription factors play critical roles in regulating early T cell development. While Notch signals are critically required at the early stage of T cell development, the completion of T cell lineage commitment is far from the initial response to Notch signaling. Other transcription factors such as PU.1, Ikaros, and RUNX1 are required to enable progenitor cells to committee T cell lineage before Notch signaling. YY1 is a ubiquitous transcription factor and mammalian Polycomb Group Protein (PcG) with important functions to regulate lymphocytes development, stem cell self-renewal, cell proliferation, and survival. Previous study showed that YY1 can interact with the Notch1 receptor intracellular domain and regulate Notch1 transactivation activities in vitro. Thus, YY1 may also belong to the core T cell lineage regulatory factors and is required for progenitor cell commitment to T cell development. To test how loss-of-function of YY1 impacts early T cell development, we utilized a conditional Yy1 knockout allele Yy1f/f with loxP sites flanking the Yy1 promoter region and exon 1. Yy1f/fmice were crossed to the inducible Mx1-Cre. In Yy1f/fMx1-Cre mice, YY1 deletion was achieved after treatment with the pI-pC. Yy1-/- mice had significantly reduced numbers of lymphoid-primed multipotent progenitor, (LMPP), common lymphoid progenitor (CLP), and double-negative (DN) T cells compared to Yy1+/+ mice. YY1 deficiency resulted in an early T cell developmental blockage at the DN1 stage. In addition, Notch1 mRNA and protein expressions were significantly reduced in Yy1-/- thymocytes compared to Yy1+/+ thymocytes. In Yy1-/- thymocytes, Notch target gene Hes1 was also downregulated. Thus, YY1 is required for early T cell development and Notch1 signaling. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Our previous results demonstrated that YY1 PcG function is required for Igκ chain rearrangement in early B cell development, however, it is not required for YY1 functions in promoting HSC self-renewal and maintaining HSC quiescence. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Herein, we utilized a YY1 REPO domain mutant (YY1ΔREPO). The small 25 amino acid REPO domain is necessary and sufficient for recruiting other PcG proteins to YY1-bound chromatin sites in Drosophila. While YY1ΔREPO is competent for DNA binding, transcriptional activation, transient transcriptional repression, and interaction with transcriptional coregulators such as HDACs, it is defective in all YY1 PcG functions and unable to recruit other PcG proteins to DNA. This mutant is therefore a powerful tool for dissecting mechanisms governing YY1 PcG-dependent versus -independent functions. Bone marrow cells from Yy1f/f Mx1-Cre mice were transduced retrovirally with MigR1-FlagYY1, MigR1-FlagYY1ΔREPO or MigR1 vector and transplanted into lethally irradiated CD45.1+ mice. In addition, Mx1-Cre bone marrow cells infected with MigR1 vector were used as the wild-type control and transplanted into CD45.1+ mice. While YY1 is required for DN1 to DN2 transition, YY1 PcG function/REPO domain is not required for DN1 transition. Instead, in mice lack of YY1 PcG function/REPO domain, early T cells had increased cell apoptosis and failed to survive. Interestingly, although YY1 PcG function/REPO domain is critical for early T cell survival, it is not required for YY1 regulation of Notch1 expression. We concluded that YY1 is a critical regulator for early T cell development and Notch signaling. There is a lineage-specific requirement for the YY1 PcG function/REPO domain for early T cell development. While YY1 PcG function is required for early T cell survival, it is not required for YY1 regulation of Notch1 expression. YY1 PcG and non-PcG functions promotes T cell development by unique mechanisms of promoting cell survival and Notch1 expression respectively. Disclosures No relevant conflicts of interest to declare.

A Hypomorphic Cbfb Allele Reveals a Critical Dosage-Sensitive Function of Core Binding Factors at the Earliest Stages of T Cell Development.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 124-124
Author(s):  
Ivan Maillard ◽  
Laleh Talebian ◽  
Zhe Li ◽  
Yalin Guo ◽  
Daisuke Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Binding ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Hematopoietic Stem

Abstract The family of core binding factors includes the DNA-binding subunits Runx1-3 and the common non-DNA binding partner CBFβ. Runx1 and CBFβ are essential for the emergence of hematopoietic stem cells during fetal development, but not for stem cell maintenance during later ontogeny. Runx1 is also required for megakaryocyte differentiation, B cell development, and for the DN2 to DN3 transition in thymocyte development. Runx2/CBFβ are critical for normal osteogenesis, and Runx3 for CD4 silencing in CD8+ T cells, but their contribution to other steps of hematopoietic development is unknown. To examine the collective role of core binding factors in hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). CBFβ protein levels were reduced by approximately 2–3 fold in fetuses homozygous for the Cbfbrss allele (Cbfbrss/rss), and 3–4 fold in fetuses carrying one hypomorphic and one knockout allele (Cbfbrss/−). Cbfbrss/rss and Cbfbrss/− fetuses had normal erythroid and B cell development, and relatively mild abnormalities in megakaryocyte and granulocyte differentiation. In contrast, T cell development was very sensitive to an incremental reduction of CBFβ levels: mature thymocytes were decreased in Cbfbrss/rss fetuses, and virtually absent in Cbfbrss/−fetuses. We next assessed the development of Cbfbrss/rss and Cbfbrss/− fetal liver progenitors after transplantation to irradiated adult recipients, in competition with wild-type (wt) bone marrow cells. Wt, Cbfbrss/rss and Cbfbrss/− fetal progenitors replenished the erythroid, myeloid and B cell compartments equally well. The overall development of Cbfbrss/rss T cells was preserved, although CD4 expression was derepressed in double negative thymocytes. In Cbfbrss/− chimeras, mature thymocytes were entirely derived from competitor cells. Furthermore, the developmental block in Cbfbrss/− progenitors was present at the earliest stages of T cell development within the DN1 (ETP) and DN2 subsets. Our data define a critical CBFβ threshold for normal T cell development, and they situate an essential role of core binding factors during the earliest stages of T cell development. In addition, early thymopoiesis appeared more severely affected by reduced CBFβ dosage than by the lack of Runx1 (Ichikawa et al., Nat Med 2004; Growney et al., Blood 2005), suggesting that Runx2/3 may contribute to core binding factor activity in the T cell lineage.

KLF4 Acts As a Tumor Suppressor in T-Acute Lymphoblastic Leukemia and Negatively Regulates Human T Cell Development and Homeostasis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2405-2405
Author(s):  
Bing Xu ◽  
Peng Li
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Development ◽  
Dependent Manner ◽  
Human T Cell

Abstract The transcription factor Kruppel-like factor 4 (KLF4) may induce tumorigenesis or suppress tumor growth in a tissue-dependent manner. We found that overexpression of KLF4 induced not only human acute T-acute lymphoblastic leukemia (T-ALL) cell lines but also primary samples from T-ALL patients to undergo apoptosis through the BCL2/BCLXL pathway in vitro. T cell-associated genes including BCL11B, GATA3, and TCF7 were negatively regulated by KLF4 overexpression. Especially, KLF4 induced SUMOylation and degradation of BCL11B. However, the KLF4-induced apoptosis in T-ALL was rescued by the in vivo microenvironment. Furthermore, the invasion capacity of T-ALL to hosts was compromised when KLF4 was overexpressed. In normal human T cells, the overexpression of KLF4 severely impaired T cell development at early stages, but the blockage of T cell development was resumed by restoration of GATA3 or ICN1. In summary, our data demonstrate that KLF4 acts as a tumor suppressor in malignant T cells and that downregulation of KLF4 may be a prerequisite for early human T cell development and homeostasis. Disclosures No relevant conflicts of interest to declare.

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice

1997 ◽  
Vol 155 (1) ◽  
pp. 165-170 ◽  
Author(s):  
R Kooijman ◽  
SC van Buul-Offers ◽  
LE Scholtens ◽  
RG Reijnen-Gresnigt ◽  
BJ Zegers
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Igf I ◽  
Dwarf Mice

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

scholarly journals Production of auto-antiidiotypic antibody during the normal immune response. VII. Analysis of the cellular basis for the increased auto-antiidiotype antibody production by aged mice.

1983 ◽  
Vol 157 (5) ◽  
pp. 1635-1645 ◽  
Author(s):  
E A Goidl ◽  
J W Choy ◽  
J J Gibbons ◽  
M E Weksler ◽  
G J Thorbecke ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Bone Marrow Cells ◽  
Aged Mice ◽  
Old Mice ◽  
Marrow Cells ◽  
Young Mice

We have previously shown that old mice produce more hapten-augmentable plaque-forming cells (PFC) than do young animals, suggesting a greater auto-antiidiotype antibody (auto anti-Id) component in their immune response. In the present studies this is confirmed serologically. The marked auto-anti-Id response of aged mice can be transferred to lethally irradiated young recipients with spleen but not bone marrow cells from old donors, suggesting that it is an intrinsic property of their peripheral B cell population and that the distribution of Id arising from the bone marrow of old and young mice is similar. In contrast with young mice the auto-anti-Id response of old animals is relatively T cell-independent and old donors do not show an increase in their ability to transfer an auto-anti-Id response after priming with TNP-F. These observations suggest that old mice behave as if already primed for auto-anti-Id production. Irradiated mice reconstituted with bone marrow cells from either young or old donors together with splenic T cells from old donors generate a relatively large auto-anti-Id response, whereas mice reconstituted with bone marrow from either young or old donors together with splenic T cells from young donors produce few hapten-augmentable PFC. It is suggested that differences in Id expression and auto-anti-Id production are the consequences of the interaction of Id (and anti-Id) arising from the marrow with anti-Id (and Id) present in the peripheral T cell population which serves as a repository of information about shifts in Id distribution, resulting from lifelong interactions with environmental and self-antigens.

scholarly journals Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 841-851 ◽  
Author(s):  
Elaine M. Sloand ◽  
Lori Mainwaring ◽  
Monika Fuhrer ◽  
Shakti Ramkissoon ◽  
Antonio M. Risitano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Cell Contact ◽  
Trisomy 8 ◽  
Marrow Cells

AbstractClinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell–dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8+ T-cell expansions of one or more T-cell receptor (TCR) Vβ subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded Vβ subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoietic culture. The negative effects of Vβ-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS.

scholarly journals Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia

2011 ◽  
Vol 79 (5) ◽  
pp. 2031-2042 ◽  
Author(s):  
Xin Shi ◽  
Ping Zhang ◽  
Gregory D. Sempowski ◽  
Judd E. Shellito
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Host Defense ◽  
Bone Marrow Cells ◽  
Central Memory ◽  
Jnk Pathway ◽  
Content Type ◽  
Enhanced Production ◽  
Marrow Cells

ABSTRACTCD4+T cells play a key role in host defense againstPneumocystisinfection. To define the role of naïve CD4+T cell production through the thymopoietic response in host defense againstPneumocystisinfection,Pneumocystis murinainfection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy.Pneumocystisinfection caused a significant increase in the number of CCR9+multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+cells was increased at 5 weeks post-Pneumocystisinfection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+T cells in all tissues examined were markedly reduced followingPneumocystisinfection. This deficiency of naïve and central memory CD4+T cells was associated with delayed pulmonary clearance ofPneumocystis. Extracts ofPneumocystisresulted in an increase in the number of CCR9+MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense againstPneumocystisinfection.

Defects in T-cell–mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector–mediated gene transfer into repopulating hematopoietic cells

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3108-3116 ◽  
Author(s):  
Ted S. Strom ◽  
Stephen J. Turner ◽  
Samita Andreansky ◽  
Haiyan Liu ◽  
Peter C. Doherty ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Bone Marrow Cells ◽  
T Cell Response ◽  
Lymphoid Cells ◽  
Wiskott Aldrich Syndrome ◽  
Marrow Cells

AbstractThe Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP— animals that received transplants of mixtures of wild type (WT) and WASP— bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP— mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP— bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP— recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell–receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.

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