scholarly journals PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

2021 ◽  
Vol 11 ◽  
Author(s):  
Ling Xu ◽  
Lian Liu ◽  
Danlin Yao ◽  
Xiangbo Zeng ◽  
Yikai Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Function ◽  
De Novo ◽  
Great Success ◽  
Combined Use ◽  
Elderly Aml ◽  
Single Positive ◽  
Immunosuppressive Microenvironment ◽  
Promote Disease Progression

Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

scholarly journals Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

2021 ◽  
Vol 12 ◽  
Author(s):  
Marianna Santopaolo ◽  
Niall Sullivan ◽  
Anita Coral Thomas ◽  
Valeria Vincenza Alvino ◽  
Lindsay B. Nicholson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cells ◽  
Insulin Sensitivity ◽  
Adaptive Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
Low Grade ◽  
Cardiac Damage

Background: Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in Type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued by treating mice with abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis. Clinical evidence indicated abatacept can slow the decline in beta-cell function.Methods: A cohort of 24 patients (12 with T2D) undergoing hip replacement surgery was enrolled in the study. Flow cytometry and cytokine analyses were performed on BM leftovers from surgery. We next compared the immune profile of db/db and control wt/db mice. In an additional study, db/db mice were randomized to receive abatacept or vehicle for 4 weeks, with endpoints being immune cell profile, indices of insulin sensitivity, and heart performance.Results: Patients with T2D showed increased frequencies of BM CD4+ (2.8-fold, p = 0.001) and CD8+ T cells (1.8-fold, p = 0.01), with the upregulation of the activation marker CD69 and the homing receptor CCR7 in CD4+ (1.64-fold, p = 0.003 and 2.27-fold, p = 0.01, respectively) and CD8+ fractions (1.79-fold, p = 0.05 and 1.69-fold, p = 0.02, respectively). These differences were confirmed in a multivariable regression model. CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T-cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and the levels of proinflammatory cytokines and improved cardiac function but not insulin sensitivity.Conclusions: Results provide proof-of-concept evidence for the activation of BM adaptive immunity in T2D. In mice, treatment with abatacept dampens the activation of adaptive immunity and protects from cardiac damage.

TECK, an Efficacious Chemoattractant for Human Thymocytes, Uses GPR-9-6/CCR9 as a Specific Receptor

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2533-2536 ◽  
Author(s):  
Byung-S. Youn ◽  
Chang H. Kim ◽  
Franklin O. Smith ◽  
Hal E. Broxmeyer
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Migration ◽  
Chemokine Receptor ◽  
Calcium Flux ◽  
Specific Receptor ◽  
Double Positive ◽  
T Cell Migration ◽  
Single Positive ◽  
Made In

Chemokines regulate leukocytes trafficking in normal and inflammation conditions. Thymus-seeding progenitors are made in bone marrow and migrate to the thymus where they undergo their maturation to antigen-specific T cells. Immature T cells are in thymic cortex, while mature thymocytes are in medulla. Chemokines may be important for homing of thymus-seeding progenitors, and/or differential thymocyte localization in thymus. Here we report that GPR-9-6, now called CC chemokine receptor 9 (CCR9), is a receptor for thymus-expressed chemokine, TECK. Among a panel of chemokines tested, TECK specifically induced calcium flux in CCR9-expressing cell lines. We also showed that TECK efficaciously induced chemotaxis of immature CD4+CD8+ double-positive, and mature CD4+ and CD8+ single-positive human thymocytes. Our data suggest that TECK/CCR9 interaction may play a pivotal role in T-cell migration in the thymus.

scholarly journals Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B

Blood ◽  
2013 ◽  
Vol 122 (14) ◽  
pp. 2346-2357 ◽  
Author(s):  
Jau-Yi Li ◽  
Jonathan Adams ◽  
Laura M. Calvi ◽  
Timothy F. Lane ◽  
M. Neale Weitzmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Progenitor Cells ◽  
Cell Function ◽  
Hemopoietic Stem Cell ◽  
Short Term ◽  
Key Points ◽  
Stem And Progenitor Cells

Key Points Ovariectomy expands short-term hemopoietic stem and progenitor cells and improves engraftment and host survival after bone marrow transplantation. T cells are required for ovariectomy to expand hemopoietic stem and progenitor cells.

Long-Term Chimerism and B-Cell Function After Bone Marrow Transplantation in Patients With Severe Combined Immunodeficiency With B Cells: A Single-Center Study of 22 Patients

Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2923-2930 ◽  
Author(s):  
Elie Haddad ◽  
Françoise Le Deist ◽  
Pierre Aucouturier ◽  
Marina Cavazzana-Calvo ◽  
Stephane Blanche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
B Cell Function ◽  
Host Origin

We retrospectively analyzed the B-cell function and leukocyte chimerism of 22 patients with severe combined immunodeficiency with B cells (B+ SCID) who survived more than 2 years after bone marrow transplantation (BMT) to determine the possible consequences of BMT procedures, leukocyte chimerism, and SCID molecular deficit on B-cell function outcome. Circulating T cells were of donor origin in all patients. In recipients of HLA-identical BMT (n = 5), monocytes were of host origin in 5 and B cells were of host origin in 4 and of mixed origin in 1. In recipients of HLA haploidentical T-cell–depleted BMT (n = 17), B cells and monocytes were of host origin in 14 and of donor origin in 3. Engraftment of B cells was found to be associated with normal B-cell function. In contrast, 10 of 18 patients with host B cells still require Ig substitution. Conditioning regimen (ie, 8 mg/kg busulfan and 200 mg/kg cyclophosphamide) was shown neither to promote B-cell and monocyte engraftment nor to affect B-cell function. Eight patients with B cells of host origin had normal B-cell function. Evidence for functional host B cells was further provided in 3 informative cases by Ig allotype determination and by the detection, in 5 studied cases, of host CD27+ memory B cells as in age-matched controls. These results strongly suggest that, in some transplanted patients, host B cells can cooperate with donor T cells to fully mature in Ig-producing cells.

scholarly journals Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Science ◽  
2019 ◽  
Vol 366 (6468) ◽  
pp. 1013-1021 ◽  
Author(s):  
Robert D. Leone ◽  
Liang Zhao ◽  
Judson M. Englert ◽  
Im-Meng Sun ◽  
Min-Hee Oh ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Effector T Cells ◽  
Tumor Immune Evasion ◽  
Metabolic Characteristics ◽  
Metabolic Plasticity ◽  
Tumor Bearing ◽  
Immunosuppressive Microenvironment

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

Heparin-Induced Thrombocytopenia Is a Thymus (T cell) Dependent Disorder.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3020-3020
Author(s):  
Shayela Suvarna ◽  
Emily K.E. McCracken ◽  
Gowthami M. Arepally
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
De Novo ◽  
Antibody Responses ◽  
Peripheral Tolerance ◽  
Immune Disorder ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Drug Dependent

Abstract Heparin-Induced Thrombocytopenia (HIT) is a drug-dependent immune disorder caused by autoantibodies to Platelet Factor 4 (PF4) and heparin. The immune basis of HIT is poorly understood. Recent studies describing transient antibody responses and absence of immunologic memory in HIT suggest that PF4/heparin autoantibodies may develop independently of T cell help. To investigate the cellular basis of the HIT immune response, we have developed a murine autoimmune model in which anti-murine PF4/heparin (anti-mP+H) arise de novo. Cohorts of BALB/c mice were immunized daily either intravenously (IV, n=10) or intraperitoneally (IP, n=10) for five days with complexes of murine (m) PF4/heparin (IV, n=5 or IP, n=5), heparin alone (IV, n= 2) or buffer (IV, n=3 or IP, n=5). Mice were screened for anti-mP+H for four weeks after immunization using a murine PF4/heparin ELISA. Peak antibody responses to antigen were seen at 11–15 days in 2/5 mice injected with IV mP+H (Day 11, mouse IV P+H #0 peak A450nm =0.34±0.01; Day15 mouse IV P+H #2 peak A450nm =0.69±0.01), and at days 22–25 in 2/5 mice injected by IP route (Day 22, mouse IP P+H #0 peak A450nm =0.37±0.01; Day 25 mouse IP P+H #2 peak A450nm =0.78±0.02). Anti-mP+H were not detected in mice injected with heparin alone or buffer alone at any time point (peak maximum IV A450nm= 0.1±0.001, Control #2; mouse IP P+H Control #2 A450nm =0.04±0.002). Serologically, murine autoantibodies were similar to anti-human (h) PF4/heparin. Anti-mP+H reactivity was specific for murine antigen (mouse IV P+H #2 A450nm=0.65±0.06), and was reduced with antigen in the presence of excess heparin (A450nm=0.38±0.01). Minimal reactivity was seen with wells coated with hP+H (A450nm=0.09±0.005), albumin (mouse IV P+H #2 A450nm=0.15±0.03), or PBS alone (mouse IV P+H #2 A450nm =0.16±0.01). Similar to human HIT antibodies, anti-mP+H were of IgG1 subclass. To determine if T cells are required for development of anti-mP+H, mice lacking T cell function (BIG:BALB/c-Nu, n=10) were injected IV with mP+H daily for five days. Unlike euthymic mice, nude mice did not manifest any antibody responses to IV injections of mP+H. In summary, we have developed a novel murine autoimmune model of anti-PF4/heparin that recapitulates many salient features of the human immune syndrome. Using this murine model, we demonstrate that T cells are essential for development PF4/heparin autoantibodies. Studies are currently underway to delineate mechanisms of T cell regulation and peripheral tolerance in HIT.

Mycophenolate Acid Has a Negative Effect on the Maturation and Immune Function of the Murine Bone Marrow-Derived Dendritic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3808-3808
Author(s):  
Zhen Cai ◽  
Wenye Huang ◽  
Wenji Sun
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Function ◽  
De Novo ◽  
Th2 Cytokines ◽  
Negative Effect ◽  
Antigen Presenting

Abstract Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, currently widely used in allogeneic bone marrow transplantation. Its active metabolite, mycophenolic acid (MPA) is a noncompetitive, reversible inhibitor of the enzyme inosine 59-monophosphate dehydrogenase, which plays a major role in the de novo synthesis of guanosine nucleotides. Unlike other cells that also use the salvage pathway for purine biosynthesis, proliferating B and T cells are dependent on the de novo pathway generate guanosine. Thus, MMF exerts its immunosuppressive effects of lymphocyte proliferation. Recently, some studies found that MPA could inhibit the immun immune function of antigen presenting cells. Dendritic cells (DCs), the most potent antigen presenting cells with the unique ability to prime naive T cells, play a central role in antigen processing and presentation to induce T cell response in vitro and in vivo. This study is to evaluate the effects of MPA, the in vivo active metabolite of MMF, on the maturation and immune function of murine bone marrow-derived dendritic cells, and to explore the underlying mechanisms of MMF in graft versus host disease. Bone marrow-derived dendritic cells (DC) were cultured with GM-CSF and IL-4 in the presence of MPA at doses of 0.01 and 0.1μmol/L. The ability of the allostimulatory activities of the DCs on allogeneic T cells was assessed by MLR. IL-12 production in culture supernatant and the Th1/Th2 cytokines such as IL-2, IFN-g, IL-4 and IL-10 levels in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assays. The activity of NF-κB in DCs was measured with Western blot assays. Our results showed that DCs cultured in the presence of MPA expressed lower levels of CD40, CD80 and CD86, exhibited weaker activity of stimulating the allogeneic T cell proliferation and weaker in antigen presenting function with a concurrent reduction of IL-12 production. MPA-treated DCs stimulated allogeneic T cells to secrete higher levels of Th2 cytokines IL-4 and IL-10 but lower levels of Th1 cytokines IL-2 and IFN-g than did DCs not treated with MPA. The activity of NF-κB was decreased in DCs treated with MPA in a dose-dependent manner. We conclude that MPA, and hence MMF, exerts a negative effect on the maturation and immune function of in vitro cultured DCs, and drives a shift of Th1 cytokines to Th2 cytokines in MLR. This negative effect is associated with a decrease in NF-κB activity. Say something about the significance of this finding regarding GVHD.

Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2195-2195
Author(s):  
William J. Murphy ◽  
Isabel Bareo ◽  
Alan M. Hanash ◽  
Lisbeth A. Welniak ◽  
Kai Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Marrow Cell ◽  
Poly I:C ◽  
Hybrid Resistance

Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy.

Exisulind Selectively Induces Apoptosis Via C-Jun Kinase Activation in MDS and sAML/MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4902-4902
Author(s):  
Akos Czibere ◽  
Wolf C. Prall ◽  
Sabine Knipp ◽  
Andrea Kuendgen ◽  
Luiz F. Zerbini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Kinase Activation ◽  
Jun Kinase ◽  
Secondary Acute Myeloid Leukemia ◽  
M Phase ◽  
De Novo Aml ◽  
Induced Apoptosis

Abstract Treatment of patients suffering from myelodysplastic syndromes (MDS) is difficult and frustrating, particularly when in progression or already progressed to secondary acute myeloid leukemia (sAML). In these cases, the bone marrow contains an increasing number of immature cells, which are characterized by reduced apoptotic and increased proliferative activity. Therefore, pro-apoptosis has recently been proposed as a novel therapeutic approach. Exisulind is a potentially pro-apoptotic agent, and therefore, we investigated its influence on proliferation, differentiation, cell cycle and apoptosis in peripheral blood-derived CD34+ stem cells (PBSC) obtained from 10 patients suffering from refractory anaemia with excess of blasts in transformation (RAEB-T), two sAML/MDS cell lines, one de-novo AML cell line and healthy CD34+ bone marrow cells. Incubation of sAML/MDS cells with Exisulind clearly inhibited colony formation in the CFU-assays. Interestingly, Exisulind did not alter the percentages of sAML/MDS cells in G1-, S-, G2-, M-phase, but reduced proliferation and induced apoptosis in this cell type. Likewise, in 8 out of 10 RAEB-T samples Exisulind significantly inhibited proliferation and increased the rate of apoptotic cells. Exisulind had no effect on de-novo AML or normal CD34+ cells. We detected increased c-Jun NH2-terminal kinase activity in sAML/MDS cells treated with Exisulind. Adding a specific JNK-inhibitor to Exisulind-treated sAML/MDS and RAEB-T cells partly abrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS and RAEB-T cells is dependent on JNK activation. We conclude that JNK is one mediator of apoptosis in MDS cells treated with Exisulind. Moreover, our data strongly suggests to explore the potential use of Exisulind as a novel, pro-apoptotic therapy for patients with RAEB-T and sAML/MDS.

Multilineage Expansion of Lymphoid and Myeloid Cells in Mice Expressing PML-RARα under the Control of the Murine Cathepsin G Locus.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2551-2551
Author(s):  
Geoffrey L. Uy ◽  
Jacqueline E. Payton ◽  
Timothy James Ley
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Cell Function ◽  
Cathepsin G ◽  
Pcr Analysis ◽  
Self Renewal ◽  
Marrow Cells

In one of our laboratory’s models of acute promyelocytic leukemia (APL), the PML-RARα fusion cDNA is knocked into the 5′ UT of the azurophil granule protease, cathepsin G. Nearly all mCG-PML-RARα mice develop lethal leukemia with promyelocytic features following a 150–400 day latent period. We originally chose the cathepsin G gene for the targeting locus because its expression was believed to be restricted to promyelocytes. However, we have now observed high levels of cathepsin G expression with gene expression profiling of leukemic bone marrow samples from patients with AML FAB M1 or M2, i.e. blasts with minimal or no differentiation (M1: n=21, mean raw expression value for cathepsin G=23,885 ± 31,737; M2: n=22, mean=24,088 ± 26,585; M3: n=14, mean 116,029 ± 47,017). To examine whether cathepsin G is normally expressed in murine hematopoietic progenitor cells, we performed gene expression arrays with highly purified Sca-1+/lin− bone marrow cells; cathepsin G mRNA was easily detected in these cells (n=4, mean cathepsin G raw expression value=9,324 ± 5,082; array average normalized to 1,500). We therefore decided to determine whether the early progenitor compartment in mCG-PML-RARα mice was expanded due to unexpected expression of the transgene in KLS (c-kit+, Lin−, Sca-1+) cells; however, no difference was detected in the frequency of marrow-derived KLS cells between mCG-PML-RARα and WT mice that were age, strain, and gender matched (0.074% vs 0.071%, p=0.89). The GMP compartment (Lin−, c-kit+, Sca1−, CD34+, FcRγ+) showed a tendency towards expansion in mCG-PML-RARα mice (0.10% vs 0.032%) but the difference was not significant (p=0.067). To better assess stem cell function in these mice, we performed a competitive repopulation study using marrow derived from Ly 5.2/mCG-PML-RARα mice mixed with Ly5.1/WT marrow cells at various ratios (1:1, 9:1, and 1:9) that were transplanted into genetically compatible hosts. Lineage markers in the peripheral blood were tested at 6, 12, and 24 weeks to assess the contribution of mCG-PML-RARα-derived progenitor and stem cells to the B, T, and myeloid lineages. As expected, we observed a highly reproducible increase in the proportion of Gr-1+ cells derived from mCG-PML-RARα donors at all time points (78.8% ± 11% donor-derived cells at a 1:1 donor: recipient ratio at 6 months, p=0.0006). Surprisingly, we also observed a reproducible increase in B220+/CD19+ cells (66.7% ± 4%, p<0.0001) and CD3+ cells from the mCG-PML-RARα donors (60.4% ± 3% p=0.0010) at 6 months, suggesting that mCG-PML-RARα also confers a growth or survival advantage to B and T cells. To determine whether cathepsin G was expressed in these compartments, we purified CD19+ B and CD3+ T cells by flow cytometry (>99% purity) and did not detect cathepsin G mRNA using a sensitive, knockout-proven qRT-PCR analysis. These data strongly suggest that both the WT cathepsin G gene and the mutant mCG-PML-RARα allele are unexpectedly expressed in the stem cell compartment, with both myeloid and lymphoid progeny of these cells displaying a growth advantage in vivo. However, lymphoid malignancies have not been detected in these mice (n>400), suggesting that PML-RARα is unable to initiate transformation in lymphocytes. Our data imply that the PML-RARα gene is activated in a multipotent compartment in this mouse model, raising the possibility that PML-RARα may not actually ‘reprogram’ progenitor cells to undergo self-renewal, but may rather initiate transformation in pluripotent cells with intrinsic self-renewal capabilities.

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