scholarly journals Characteristics of the TCR Vbeta Repertoire and Identical Clonally Expanded T Cells in Chronic Myeloid Leukemia Patients in Advanced Phase with ABL Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5136-5136
Author(s):  
Ling Xu ◽  
Yuhong Lu ◽  
Jing Lai ◽  
Wei Yu ◽  
Zhenyi Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytotoxic Lymphocyte ◽  
Advanced Phase

Abstract Abstract Tumor specific or related antigen cytotoxic lymphocyte (CTL) have been identified in chronic myeloid leukemia patients, however, whether they are constituted by specific type of T cell receptor chains has not been illustrated so far. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 5 CML patients in blast crisis (BC-CML) and one in acceleration phase (AP-CML) with ABL kinase domain mutations (KDMs) including T315I, E255K, F317L+S417Y, Y-253F and L387M+T-315A. Examination of TCR Vβ expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) combined with GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in those patients, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample, which distributed in 15/24 different subfamilies (TCR Vβ4, Vβ5, Vβ6, β8, Vβ9, Vβ10, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ21, Vβ22, Vβ23, Vβ24). Intriguingly, a relatively highly expanded Vβ9 clone with the same length as CDR3 (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the other two CML patient in myeloid blast crisis (MBC-CML) or the one CML patients in accelerated phase. In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency status of these patients, and clonally expanded Vβ9 T cell clones may represent a specific immune response to leukemia-associated antigens in LBC-CML patients. Disclosures Li: The Foundation for High-level Talents in Higher Education of Guangdong, China ([2013]246-54),and the Guangzhou Science and Technology Project Foundation (201510010211): Research Funding; National Natural Science Foundation of China (81270604, U1301226, and 81400109), the Guangdong Natural Science Foundation (S2013040016151 and S2013020012863): Research Funding.

scholarly journals T cell lineage involvement in lymphoid blast crisis of chronic myeloid leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1155-1161 ◽  
Author(s):  
M Allouche ◽  
A Bourinbaiar ◽  
V Georgoulias ◽  
R Consolini ◽  
A Salvatore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Cell Lineage ◽  
Virtual Absence ◽  
Hodgkin's Lymphomas

Cytochemical and immunologic analysis of cells obtained from two patients with chronic myeloid leukemia (CML) during blast crisis reveals markers suggestive of an immature lymphoid phenotype. Peripheral blood mononuclear cells from both patients generated spontaneous lymphoblastoid colonies in methylcellulose, a phenomenon observed in T cell acute lymphoblastic leukemias and T cell non- Hodgkin's lymphomas but not in any other type of leukemia. Colonies derived from one patient were composed predominantly of OKT3+ cells (89%), whereas those from the second patient displayed 42% OKT3+ and OKT6+ cells. In the second patient's colonies, each of five mitoses contained the Philadelphia chromosome (Ph1) and two of five displayed the same additional karyotypic abnormalities as the blast crisis cells. Cells obtained from the two patients during remission still gave rise to spontaneous T cell colonies (greater than 85% OKT3+) and Ph1 was detected in 33% and 60% of the metaphases, respectively. However, when colony growth was induced by an interleukin 2-containing conditioned medium, less than 5% of mitoses were Ph1-positive. These data suggest that: (1) the T cell lineage might be involved in CML; (2) a subset of T cells may remain unaffected by the leukemic process, as demonstrated by the virtual absence of Ph1 in induced T cell colonies; and (3) the spontaneous colony assay seems to select for the growth of malignant T cells.

Immunoprofile of Patients with Chronic Myeloid Leukemia Treated with Imatinib, Nilotinib or Dasatinib,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3764-3764
Author(s):  
Yoshiki Hayashi ◽  
Hirohisa Nakamae ◽  
Takako Katayama ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Nk Cell ◽  
Chronic Phase ◽  
Interquartile Range ◽  
Cell Reactivity ◽  
Gm Csf

Abstract Abstract 3764 Recent reports showed that dasatinib induces significant immunostimulation with clonal expansion of large granular lymphocytes (LGL) which, in chronic myeloid leukemia (CML), is related to both better prognosis and to autoimmune-like side effects. It is speculated that lower levels of circulating T-regulatory cells play a partial role in LGL proliferation in patients receiving dasatinib. The immunoprofile was studied using flow cytometry to evaluate lymphocyte subsets and NK-cell reactivity in the peripheral blood of 61 patients in the chronic phase of CML during treatment with a tyrosine kinase inhibitor (TKI) (Median age: 58 years; imatinib 36, nilotinib 9, dasatinib 16). Furthermore, we measured plasma levels of 27 types of cytokines or chemokines in 58 patients in the chronic phase of CML so that a comprehensive comparison could be made of the differences in immunoprofile among the patients receiving these three TKIs. There were no significant differences between the three TKI-treated groups in terms of CD4/8 ratios or the number of T-cells (CD3+CD8+ or CD4+) and NK cells (CD3-CD56+). However, the number of NK-LGL (CD56+CD57+) and T-LGL (CD3+CD57+) increased significantly in the group that received dasatinib. Furthermore, dasatinib significantly enhanced NK-cell reactivity as compared to imatinib and nilotinib. In contrast nilotinib significantly suppressed NK-cell reactivity (E/T ratio =10:1: Median (interquartile range), 8.7% (5.0–16.2), 5.2% (4.8–11.4), 20.8% (13.4–33.3), for imatinib, nilotinib and dasatinib, respectively). In addition, the number of regulatory T-cells (CD4+CD25int-hiCD127low) was similar among the three groups (Median (interquartile range), 36/mm3 (27–53), 48/mm3 (34–60), 39/mm3 (26–53), for imatinib, nilotinib and dasatinib, respectively). Furthermore, in the analysis of cytokines and chemokines, plasma levels of IL-8, IP-10, and MCP-1 were significantly elevated while the level of PDGF-bb was significantly decreased in all three groups compared to those of healthy control. Plasma levels of IL-1 beta, IFN-gamma, and FGF-basic were significantly decreased in only the dasatinib group compared to those of control (P=.02, P=.04, P=.03, respectively). In addition, plasma levels of GM-CSF were significantly elevated in the imatinib and dasatinib groups (Median (interquartile range), 6.1 pg/ml (2.7–11.7) and 7.9 pg/ml (4.5–8.2), P=.02, and P=.03, respectively) but not in the nilotinib group (P=.34) when compared to those of control. In the multiple regression analysis that evaluated the relationship between NK-reactivity and cytokines or chemokines in the patients receiving dasatinib, only plasma levels of GM-CSF were significantly associated with NK-reactivity (P=.03). Notably, in our data, dasatinib and nilotinib exerted opposite effects on NK-cell reactivity, expansion of LGL, and showed different cytokine and chemokine profiles. Based on our results, the activation of NK-cell reactivity induced by dasatinib might be caused by a mechanism other than a decrease in the number of regulatory T-cells. Additionally, in an unphysiological immunological status mediated by dasatinib, GM-CSF might make some contribution to NK-cell reactivity. Disclosures: Nakamae: BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Hino:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 380-383 ◽  
Author(s):  
Mohamad Mohty ◽  
Agnes S. M. Yong ◽  
Richard M. Szydlo ◽  
Jane F. Apperley ◽  
Junia V. Melo
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Polycomb Group ◽  
Peripheral Blood Mononuclear ◽  
Advanced Phase ◽  
Therapeutic Decisions

Because the polycomb group gene BMI1 regulates the proliferation of both normal and leukemic stem cells, we examined whether BMI1 expression was associated with disease progression in chronic myeloid leukemia (CML). Levels of BMI1 RNA were significantly higher in patients with advanced-phase than in patients with chronic-phase CML in both CD34+ cells (P = .006) and total peripheral-blood mononuclear cells (P < .001). E2F1, a transcription factor regulating BMI1, was up-regulated in CML compared with controls (P = .001). In a cohort of 64 CML patients, the level of BMI1 at diagnosis correlated with time to transformation to blast crisis, and the combination of low BMI1 and high proteinase-3 expression was associated in multivariate analysis with an improved overall survival (P = .001). We conclude that BMI1 may be a biomarker for the intrinsic heterogeneity of CML, and its measurement at diagnosis can help predict overall survival and thus contribute to better therapeutic decisions.

Dysexpression of TCRζ Related Genes in the Patients with Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4832-4832
Author(s):  
Xianfeng Zha ◽  
Xiaojuan Yan ◽  
Qi Shen ◽  
Xiuli Wu ◽  
Shaohua Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Expression Pattern ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Guangdong Province ◽  
Splicing Factor ◽  
Healthy Individuals ◽  
Expression Levels

Abstract Abstract 4832 T-cell immunodeficiency is a common feature in patients with chronic myeloid leukemia (CML), and deficiency in CD3 levels was detected in T cells from these patients, which may represent a characteristic that is related to lower T cell activation. Based on our previous finding that the expression level of the TCRζ chain gene was decreased significantly in CML, we further investigated the expression pattern of the TCRζ regulating factors. TCRζ 3′ untranslated region (3′-UTR) and the alternative splicing factor/splicing factor 2 (ASF/SF-2), to evaluate the regulating effect of ASF/SF-2 on the formation of TCRζ 3′-UTR. Moreover, the expression levels and the correlations of the FcεRIγ gene, which has a complementary to TCRζ, and the TCRζ downstream ZAP-70 gene, were analyzed. The TCRζ 3′-UTR were amplified from peripheral blood mononuclear cells (PBMCs) in 14 healthy individuals, 40 cases with CML and 22 cases with CML-CR by RT-PCR, and the splice variants of TCRζ 3′-UTR were identified. The expression levels of TCRζ, FcεRIγ, ASF/SF-2 gene and ZAP-70 gene were analyzed by real-time quantitative PCR. The results showed that two types of spliceosome: wild typed TCRζ 3′-UTR (906 bp) and alternative spliced TCRζ 3′-UTR (344 bp) could be detected in all healthy individuals. However, 35% of CML cases contained only the wild typed TCRζ 3′-UTR, which was significantly different from healthy individuals and CML-CR groups (p<0.001, p<0.001). The expression of TCRζ gene in CML group was significantly lower than healthy individuals and CML-CR groups (p=0.001,p<0.001), while significantly higher expression of FcεRIγ gene(p<0.001,p<0.001)and ASF/SF-2 (p=0.016,p<0.001) were found in CML group. According to the TCRζ 3′-UTR spliceosome feature, the CML patients were divided in two subgroups, patients who contained only the wild typed TCRζ 3′-UTR named as WT+AS− CML group, and patients who contained two types of TCRζ 3′-UTR named as WT+AS+ CML group. Significantly higher expression levels of ASF/SF-2 and FcεRIγ genes were found in WT+AS−CML group in comparison with WT+AS+ CML group (p=0.003,p=0.001), while the expression levels of TCRζ and ZAP-70 were decreased in WT+AS−CML group (Fig 1). In conclusions, the defective expression of TCRζ in CML might relate to the overexpression of ASF/SF2, which alternatively spliced the expression of TCRζ3′-UTR. The upregulation of FcεRIγ gene may overcome the defective status of TCRζ in a certain degree. Figure 1. Different expression pattern of ASF/SF-2, TCRζ, ZAP-70 and FcεRIγ genes in WT+AS-CML and WT+AS+CML. Figure 1. Different expression pattern of ASF/SF-2, TCRζ, ZAP-70 and FcεRIγ genes in WT+AS-CML and WT+AS+CML. Disclosures: Chen: Fundamental Research Funds for the Central Universities (No. 21611447, 21612116): Research Funding. Li:Fundamental Research Funds for the Central Universities (No. 21611447, 21612116): Research Funding; Natural Science Foundation of Guangdong Province, China (No. 9251063201000001): Research Funding; National Natural Science Foundation of China (No. 81100353): Research Funding; Medical Science Foundation of Guangdong Province (A2011325): Research Funding.

scholarly journals Characterization of mixed chimerism in patients with chronic myeloid leukemia transplanted with T-cell-depleted bone marrow: involvement of different hematologic lineages before and after relapse

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 243-248 ◽  
Author(s):  
E Roux ◽  
K Abdi ◽  
D Speiser ◽  
C Helg ◽  
B Chapuis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Polymerase Chain Reaction Amplification ◽  
Bone Marrow Involvement ◽  
Chronic Phase ◽  
Mixed Chimerism

Abstract We have characterized mixed chimerism (MC) in five patients with chronic myeloid leukemia (CML) who received transplants with T-cell- depleted bone marrow (BM) and who relapsed within 4 years after transplantation. To study the possible relation of MC with relapse, we purified different populations of leukocytes and analyzed their donor/recipient origin by a method based on polymerase chain reaction amplification of minisatellite DNA regions. Our results show that before relapse, all hematopoietic recipient cells are T cells, whereas monocytes, B, and natural killer (NK) cells are of donor origin. This observation does not appear to be specific for CML as similar results were found in two control patients with acute myeloid leukemia (AML). At the time of (CML) relapse, recipient granulocytes, monocytes, and erythrocytes appeared and progressively replaced the respective lineages of donor origin. No other lineages seemed to be involved as B cells and NK cells remained of donor origin and no significant changes in the number of recipient T cells were detected. In this respect relapse of CML after BM transplantation (BMT) seems not to be very different from the primary disease in chronic phase before transplantation. Furthermore, we conclude that after BMT, an association between mixed chimerism before relapse and the (CML) relapse does exist because both phenomena are consequences of T-cell depletion of the BM graft. However, this correlation might well be indirect as the MC caused by the recipient T cells appears to be independent of the one caused by the recurrent disease.

scholarly journals T cell lineage involvement in lymphoid blast crisis of chronic myeloid leukemia

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1155-1161 ◽  
Author(s):  
M Allouche ◽  
A Bourinbaiar ◽  
V Georgoulias ◽  
R Consolini ◽  
A Salvatore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Interleukin 2 ◽  
Philadelphia Chromosome ◽  
Cell Lineage ◽  
Virtual Absence ◽  
Hodgkin's Lymphomas

Abstract Cytochemical and immunologic analysis of cells obtained from two patients with chronic myeloid leukemia (CML) during blast crisis reveals markers suggestive of an immature lymphoid phenotype. Peripheral blood mononuclear cells from both patients generated spontaneous lymphoblastoid colonies in methylcellulose, a phenomenon observed in T cell acute lymphoblastic leukemias and T cell non- Hodgkin's lymphomas but not in any other type of leukemia. Colonies derived from one patient were composed predominantly of OKT3+ cells (89%), whereas those from the second patient displayed 42% OKT3+ and OKT6+ cells. In the second patient's colonies, each of five mitoses contained the Philadelphia chromosome (Ph1) and two of five displayed the same additional karyotypic abnormalities as the blast crisis cells. Cells obtained from the two patients during remission still gave rise to spontaneous T cell colonies (greater than 85% OKT3+) and Ph1 was detected in 33% and 60% of the metaphases, respectively. However, when colony growth was induced by an interleukin 2-containing conditioned medium, less than 5% of mitoses were Ph1-positive. These data suggest that: (1) the T cell lineage might be involved in CML; (2) a subset of T cells may remain unaffected by the leukemic process, as demonstrated by the virtual absence of Ph1 in induced T cell colonies; and (3) the spontaneous colony assay seems to select for the growth of malignant T cells.

scholarly journals Results of a Single Center Survey on Vaccination Against COVID-19 in Patients with Chronic Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4604-4604
Author(s):  
Ekaterina Yu. Chelysheva ◽  
Anna Petrova ◽  
Oleg A. Shukhov ◽  
Margarita Gurianova ◽  
Anastasiya Bykova ◽  
...  
Keyword(s):  
Higher Education ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Concomitant Disease ◽  
Advanced Phase ◽  
History Of ◽  
June July

Abstract Introduction Despite the availability of vaccination against COVID 19 for all population categories since January 2021, it is moving slowly in Russia. Patients (pts) with chronic myeloid leukemia (CML) usually lead a normal life with social interactions. In the context of the COVID 19 pandemic, we find it important to identify the factors of adherence to vaccination and clarify the concerns. Objective: To determine the proportion of CML pts willing to consider vaccination against COVID 19, adherence factors and reasons for not vaccinating. Materials and methods. A survey on the attitude to vaccination against COVID 19 was prospectively carried out among all pts with CML consulted at the outpatient department of National Research Center for Hematology (Moscow, Russia) who agreed to participate. The key questions included considerations for and against vaccination, socio-demographic and clinical characteristics, lifestyle, comorbidities and history of COVID 19. Results. Within 4 months (from March 15 to July 19, 2021), 172 CML pts completed the questionnaire. CML chronic phase, advanced phase and blast crisis were in 167 (97%), 4 (2%) and 1(1%) respectively. In total, 141 (82%) pts were on therapy with 1 st, 2 nd and &gt;3 rd therapy line in 77 (55%), 33 (23%) and 31 (22%) pts, respectively. Thirty one (18%) had no therapy: 6 (3.5%) newly diagnozed, 25 (14.5%) in a treatment-free remission. A deep and major molecular response was in 77 (45%) and 30 (17%) pts, respectively. Presence and absence of molecular response MR2 was in 20 (12%) and 45 (26%) pts respectively. The median age of pts was 46 years (range 19-82), 75(44%) were males. Married 108 (63%), 70 (41%) lived with elderly relatives, 35 (20%) with children. A higher education was in 123 (72%) pts, 123 (72%) could not work remotely and 46 (27%) had interactions to people by work. Any comorbidity was in 89 (52%) pts, 42(24%) had &gt;1 concomitant disease, 48 (28%) had cardiovascular diseases, 44 (26%) had an obesity. A history of COVID 19 was in 41 (24%) pts and in the close circle of 74 (43%) pts. Vaccination was supported by 94(55%) pts (with 29 (17%) already vaccinated) and not supported by 76 (44%) pts, 2 (1%) pts did not answer. Among those supporting vaccination vs not supporting there was significantly more males (52% vs 33%, p=0,012), married pts (73% vs 49%, p&lt;0,001) and pts with higher education (88% vs 51%, p=0,006). Other factors (age, comorbidities, obesity, profession-related features, COVID 19 in pts or their environment, living with elderly relatives or children, therapy and treatment response) were not significant. Less pts were against vaccination in June-July 2021 before the 3 rd outbreak of COVID 19 compared to spring period (33% vs 50%, p=0,045). The two most common reasons to avoid vaccination were the fear of complications in 37(49%) pts and waiting for additional data in 19(25%) (Fig.1). Notably, 7 (9%) pts considered CML as a contraindication to vaccination. Among those supporting vaccination, 55(59%) preferred to choose the GamCovidVac (Sputnik V) vaccine, 20(21%) had no preference (Fig.2). Out of 32 pts who gave the rationale for the Sputnik V choice 19(59%) noted its best availability, study or popularity (Fig.3). Among 23 pts with additional questions 12 (52%) wondered about the possibility of vaccination with CML diagnosis and 6 (26%) asked help with a vaccine choice. Conclusion: Despite access to vaccines against COVID 19 with proven efficacy and safety, almost half of CML pts (44%) do not support vaccination. Socio-demographic factors such as gender, education, marriage status appeared to be significant for this decision. Considering the frequent concerns of the possibility of vaccination with CML diagnosis as well as the fear of complications, hematologists should provide a relevant clarifying information on these issues. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Kokhno: Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Turkina: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

scholarly journals Characterization of mixed chimerism in patients with chronic myeloid leukemia transplanted with T-cell-depleted bone marrow: involvement of different hematologic lineages before and after relapse

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 243-248 ◽  
Author(s):  
E Roux ◽  
K Abdi ◽  
D Speiser ◽  
C Helg ◽  
B Chapuis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Polymerase Chain Reaction Amplification ◽  
Bone Marrow Involvement ◽  
Chronic Phase ◽  
Mixed Chimerism

We have characterized mixed chimerism (MC) in five patients with chronic myeloid leukemia (CML) who received transplants with T-cell- depleted bone marrow (BM) and who relapsed within 4 years after transplantation. To study the possible relation of MC with relapse, we purified different populations of leukocytes and analyzed their donor/recipient origin by a method based on polymerase chain reaction amplification of minisatellite DNA regions. Our results show that before relapse, all hematopoietic recipient cells are T cells, whereas monocytes, B, and natural killer (NK) cells are of donor origin. This observation does not appear to be specific for CML as similar results were found in two control patients with acute myeloid leukemia (AML). At the time of (CML) relapse, recipient granulocytes, monocytes, and erythrocytes appeared and progressively replaced the respective lineages of donor origin. No other lineages seemed to be involved as B cells and NK cells remained of donor origin and no significant changes in the number of recipient T cells were detected. In this respect relapse of CML after BM transplantation (BMT) seems not to be very different from the primary disease in chronic phase before transplantation. Furthermore, we conclude that after BMT, an association between mixed chimerism before relapse and the (CML) relapse does exist because both phenomena are consequences of T-cell depletion of the BM graft. However, this correlation might well be indirect as the MC caused by the recipient T cells appears to be independent of the one caused by the recurrent disease.

Programmed death 1 signaling on chronic myeloid leukemia–specific T cells results in T-cell exhaustion and disease progression

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1528-1536 ◽  
Author(s):  
Sabine Mumprecht ◽  
Christian Schürch ◽  
Juerg Schwaller ◽  
Max Solenthaler ◽  
Adrian F. Ochsenbein
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Interferon Γ ◽  
Myeloproliferative Disease ◽  
Specific Ctls ◽  
Programmed Death ◽  
Programmed Death 1

Abstract Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-γ or tumor necrosis factor-α or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking the PD-1/PD-L1 interaction by generating bcCML in PD-1–deficient mice or by repetitive administration of αPD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8+ T cells from CML patients. Taken together, our results suggest that blocking the PD-1/PD-L1 interaction may restore the function of CML-specific CTLs and may represent a novel therapeutic approach for CML.

scholarly journals Characterization of Changes in the T-Cell Receptor Repertoire in Patients with Acute Myeloid Leukemia with Durable Remission Following Allogeneic Stem Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5186-5186
Author(s):  
Ronald M. Paranal ◽  
Hagop M. Kantarjian ◽  
Alexandre Reuben ◽  
Celine Kerros ◽  
Priya Koppikar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Donor T Cells ◽  
Durable Remission

Introduction: Allogeneic hematopoietic stem-cell transplantation (HSCT) is curative for many patients with advanced hematologic cancers, including adverse-risk acute myeloid leukemia (AML). This is principally through the induction of a graft-versus-leukemia (GVL) immune effect, mediated by donor T-cells. The incredible diversity and specificity of T-cells is due to rearrangement between V, D, and J regions and the random insertion/deletion of nucleotides, taking place in the hypervariable complementarity determining region 3 (CD3) of the T-cell receptor (TCR). Massively parallel sequencing of CDR3 allows for a detailed understanding of the T-cell repertoire, an area relatively unexplored in AML. Therefore, we sought out to characterize the T-cell repertoire in AML before and after HSCT, specifically for those with a durable remission. Methods: We identified 45 bone marrow biopsy samples, paired pre- and post-HSCT, from 14 patients with AML in remission for > 2 years as of last follow-up. We next performed immunosequencing of the TCRβ repertoire (Adaptive Biotechnologies). DNA was amplified in a bias-controlled multiplex PCR, resulting in amplification of rearranged VDJ segments, followed by high-throughput sequencing. Resultant sequences were collapsed and filtered in order to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region. We next employed various metrics to characterize changes in the TCR repertoire: (1) clonality (range: 0-1; values closer to 1 indicate a more oligoclonal repertoire), it accounts for both the number of unique clonotypes and the extent to which a few clonotypes dominate the repertoire; (2) richness with a higher number indicating a more diverse repertoire with more unique rearrangements); (3) overlap (range: 0-1; with 1 being an identical T-cell repertoire). All calculations were done using the ImmunoSeq Analyzer software. Results: The median age of patients included in this cohort was 58 years (range: 31-69). Six patient (43%) had a matched related donor, and 8 (57%) had a matched unrelated donor. Baseline characteristics are summarized in Figure 1A. Six samples were excluded from further analysis due to quality. TCR richness did not differ comparing pre- and post-HSCT, with a median number pre-HSCT of 3566 unique sequences (range: 1282-22509) vs 3720 (range: 1540-12879) post-HSCT (P = 0.7). In order to assess whether there was expansion of certain T-cell clones following HSCT, we employed several metrics and all were indicative of an increase in clonality (Figure 2B). Productive clonality, a measure of reactivity, was significantly higher in post-transplant samples (0.09 vs 0.02, P = 0.003). This is a measure that would predict expansion of sequences likely to produce functional TCRs. The Maximum Productive Frequency Index was higher post-HSCT indicating that the increase in clonality was driven by the top clone (most prevalent per sample). Similarly for the Simpson's Dominance index, another marker of clonality which was higher post-HSCT (0.01 vs 0.0009, P = 0.04). In order to determine whether this clonal expansion was driven by TCR clones shared among patients, we compared the degree of overlap in unique sequences among pre and post-HSCT samples. We found there was very little overlap between samples in the pre and the post-transplant setting and no change in the Morisita and Jaccard Overlap Indices. Conclusions: In conclusion, we show in this analysis an increase in clonality of T-cells following HSCT in patients with AML. This is likely related to the GVL effect after recognition of leukemia antigens by donor T cells and subsequent expansion of these T-cells. These expanded T-cell clonotypes were unlikely to be shared by patients in this cohort, likely reflecting the variety of antigens leading to the GVL effect. This could have direct implications on TCR-mediated immune-therapies given the likely need for a personalized, patient-specific design for these therapies. Figure 1 Disclosures Kantarjian: BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties.

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