scholarly journals K-RasG12D–induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to γ-secretase inhibitors

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3373-3382 ◽  
Author(s):  
Thomas Kindler ◽  
Melanie G. Cornejo ◽  
Claudia Scholl ◽  
Jianing Liu ◽  
Dena S. Leeman ◽  
...  
Keyword(s):  
T Cell ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Mapk Pathway ◽  
Notch Pathway ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Double Positive ◽  
The Impact ◽  
Notch1 Mutations

Abstract To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-RasG12D murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to γ-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways.

scholarly journals Downregulating Notch Signaling in KrasG12D/+ Mice Inhibits Both T-Cell Leukemia and Myeloproliferative Neoplasm in a Cell-Autonomous Manner

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 261-261
Author(s):  
Guangyao Kong ◽  
Yuan-I Chang ◽  
Erik A. Ranheim ◽  
Yun Zhou ◽  
Yangang Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Notch Signaling ◽  
Bone Marrow Cells ◽  
Hematopoietic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
A Cell ◽  
Notch1 Mutations

Abstract Notch signaling is implicated in diverse functions in hematopoiesis, including stem cell maintenance, cell fate specification, cell proliferation, and apoptosis. Aberrant Notch signaling is associated with the pathogenesis of various hematopoietic malignancies. NOTCH1 mutations that lead to elevated intracellular Notch1 activity are identified in 50-60% of patients with acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) and in 100% of oncogenic Ras-induced T-ALL in mice. Although Notch1 mutations contribute to the malignant transformation of normal T-cells to T-cell leukemia/lymphoma initiating cells in the KrasG12D/+-induced T-ALL model, it remains unclear whether Notch1 signaling is necessary for T-ALL genesis. Moreover, it remains controversial whether loss of Notch signaling promotes myeloproliferative neoplasms (MPN) in a cell-autonomous manner. To address these questions, we used genetic approaches to downregulate Notch signaling in KrasG12D/+ mice, which develop both T-ALL and MPN. Downregulation of Notch signaling in hematopoietic cells is achieved through Mx1-Cre–mediated conditional expression of Rosa26-GFP-dnMAML1, which inhibits canonical Notch signaling, or conditional knockout of Pofut1, which catalyzes O-fucosylation of Notch receptors and modulates Notch receptor ligand interactions. We found that either overexpression of dnMAML1 or deletion of Pofut1 significantly enhanced MPN phenotypes and shortened the survival of KrasG12D/+ mice. However, several pieces of evidence suggest that downregulation of Notch signaling in non-hematopoietic cells might influence MPN development. First, 100% of compound mice developed atopic dermatitis-like disease that is shown to promote MPN in a cell non-autonomous manner. Second, ~30% of endothelial cells were GFP-positive (expressing dnMAML1) in KrasG12D/+; Rosa26GFP-dnMAML1/+ mice. To determine whether downregulating Notch signaling prevents T-ALL and/or promotes MPN in a cell-autonomous manner, we transplanted the same number of KrasG12D/+, KrasG12D/+; Rosa26GFP-dnMAML1/+, or KrasG12D/+; Pofut1-/- bone marrow cells (CD45.2+) along with congeneic competitor cells (CD45.1+) into lethally irradiated mice (CD45.1+). As expected, inhibiting Notch signaling significantly blocked T-cell development and completely prevented T-ALL development in recipients; T-ALL that developed in a fraction of recipient mice were derived from rare donor cells that expressed oncogenic Kras and preserved intact Notch signaling. Surprisingly, we found that the percentage of donor-derived myeloid cells was significantly lower in recipients transplanted with KrasG12D/+; Rosa26GFP-dnMAML1/+ or KrasG12D/+; Pofut1-/- bone marrow cells and consequently none of them developed donor-derived MPN-like disease. In contrast, ~20% of the recipient mice transplanted with KrasG12D/+ cells developed a lethal, donor-derived MPN (P=0.02). Because the hematopoietic stem cell (HSC) frequency was significantly lower in KrasG12D/+; Rosa26GFP-dnMAML1/+ bone marrow than that in KrasG12D/+ bone marrow, we investigated whether the absence of the MPN was due to the reduced HSC reconstitution in recipients. To normalize for HSC numbers, we transplanted lethally irradiated mice with same number of KrasG12D/+ or KrasG12D/+; Rosa26GFP-dnMAML1/+ splenocytes, which contained similar numbers of HSCs mobilized from the bone marrow. Consistent with our previous observation, only 1 out of 12 recipient mice with KrasG12D/+; Rosa26GFP-dnMAML1/+ cells developed a donor-derived (KrasG12D/+; Rosa26GFP-dnMAML1/+) MPN disease, while 6 out of 12 recipient mice with KrasG12D/+ cells died with donor-derived MPN (P=0.02). Together, our results indicate that blocking Notch signaling inhibits both T-ALL and MPN development in a cell-autonomous manner. We are currently working on the underlying mechnisms. Disclosures No relevant conflicts of interest to declare.

Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2524-2524 ◽  
Author(s):  
Juan Carlos Ramos ◽  
Luis M. Diaz ◽  
Michele Manrique ◽  
Rosangela Lima ◽  
Ngoc L Toomey ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Target Genes ◽  
Recent Analysis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Resistant Disease

Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported.

scholarly journals Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2643-2643 ◽  
Author(s):  
Keisuke Kataoka ◽  
Yasunobu Nagata ◽  
Akira Kitanaka ◽  
Jun-ichirou Yasunaga ◽  
Masako Iwanaga ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Genetic Profiling ◽  
Adult T Cell Leukemia ◽  
Disease Subtype ◽  
The Impact

Abstract Adult T-cell leukemia/lymphoma (ATL) is a distinct subtype of peripheral T-cell neoplasms associated with human T-cell leukemia virus type-1 retrovirus. ATL includes a heterogeneous group of patients in terms of pathological and clinical features as well as prognosis, suggesting the presence of underlying molecular pathogenesis that could explain such heterogeneity among patients. Recently, we performed an integrated molecular analysis of a large number of ATL cases and delineated a comprehensive registry of gene mutations and other genetic/epigenetic lesions in ATL. In this study, we investigated possible correlations between these genetic/epigenetic lesions and clinical/pathological phenotypes in a large set of ATL patients, with a special focus on the impact of mutations and copy number alterations (CNAs) on clinical outcome. We analyzed a total of 361 ATL samples, including acute (n = 192), lymphoma (n = 66), chronic (n = 89), and smoldering (n = 14) subtypes, for recurrent mutations and CNAs. Each subtype had characteristic genetic/epigenetic features, suggesting a distinct molecular pathogenesis therein. Aggressive (acute and lymphoma) subtypes were characterized by a higher number of mutations and CNAs including focal amplifications/deletions, hyperploid status, and CIMP phenotype, compared with indolent (chronic and smoldering) tumors. Two mutations (TP53 and IRF4) and eight focal deletions involving 1p13 (CD58), 6p21 (HLA-B), 9p21 (CDKN2A), 10p11 (CCDC7), 13q32 (GPR183), 16q23 (WWOX), 17p13 (TP53), and 19q13 (CEBPA), were more common in aggressive ATL than in indolent ATL. In contrast, showing a similar mutational distribution to those found in large granular lymphocytic leukemia, STAT3 mutations were characteristic of the indolent diseases. Gene set enrichment analysis of RNA-seq data showed a significant enrichment of MYC pathway and genes regulating cell cycle and DNA repair in upregulated genes in aggressive ATL. Next, we assessed the impact of mutations and CNVs on prognosis among 215 ATL cases, for which survival data were available. In the entire cohort, mutation in CCR4 and IRF4, focal amplification in 9p24 (CD274) and 14q32 (BCL11B), and focal deletion in 9p21 (CDKN2A) were found to be significant predictors of poor overall survival, after adjustment for disease subtype and age. Multivariate analysis revealed that disease subtype (aggressive vs. indolent) was the most significant predictor of clinical outcome in ATL. Subsequent multivariate analysis according to disease subtype showed that within the patients with aggressive ATL, older age (≥ 70 years), CCR4 mutations, and 9p24 amplification were independently associated with an adverse outcome. Based on the number of the risk factors they owned, patients with aggressive ATL were classified into three categories showing marked difference in 3-year overall survival (OS) (P < 0.001): those with no risk factors (OS, 32%), with one risk factor (18%), and with two or more (0%). Among the patients with indolent ATL, we found IRF4 and TP53 mutations, 9p24 amplification, and deletions in 9p21 and 10p11 were independently associated with reduced survival. Interestingly, these alterations, except for 9p24 amplification, were also identified as genes more frequent in aggressive ATL. More importantly, based on these risk factors, the patients with indolent ATL can be classified into two categories showing very different prognostic profiles: patients with no risk factors (OS, 89%) and those with one or more risk factors (21%) (P < 0.001, HR = 16.8, 95% CI:5.4-52.5), suggesting that patients with indolent ATL having a genetic feature of the aggressive subtypes might genetically and biologically represent a distinct subset, which should be better managed as having an aggressive disease. Among these poor prognostic factors, 9p24 amplification and CCR4 mutation are especially interesting, because these lesions might be plausible targets of available agents, including anti-PD1/PD-L1 and anti-CCR4 antibodies. In conclusion, based on the comprehensive genetic profiling, we demonstrated that the known subtypes of ATL can be further classified into genetically and biologically distinct subsets of tumors characterized by discrete sets of genetic lesions and substantially different prognosis. Our results suggest that molecular profiling can improve the prediction of prognosis in ATL patients and better guide therapy. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Shin-bio: Honoraria; Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.

The Role of IL7R in the Induction and Maintenance of T-Cell Leukemia/Lymphoma in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 116-116
Author(s):  
Ana Silva ◽  
Joao T. Barata ◽  
Benedict Seddon
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Tumor Development ◽  
Cell Development ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
T Cell Leukemogenesis ◽  
The Impact

Abstract Abstract 116 Interleukin 7 (IL-7) and its receptor, a heterodimer constituted by IL-7Rα (hereafter referred to as IL7R) and γc subunits, are essential for normal T-cell development and homeostasis. While it is known for long that IL7R genetic inactivation leads to severe combined immunodeficiency, only recently we and others have found IL7R gain-of-function mutations in T-cell acute lymphoblastic leukemia (T-ALL). In agreement with an oncogenic role for deregulated IL-7/IL7R signaling, IL-7 transgenic mice develop lymphomas and we have shown that xenotransplant models of human T-ALL rely on microenvironmental IL-7 for tumor acceleration. These studies have highlighted the importance of keeping IL7R-mediated signaling within physiological levels. Indeed, throughout normal T-cell development IL7R expression at the cell surface is tightly controlled and there is correlative evidence, from studies in AKR/J mice, that high IL7R levels in developing thymocytes can promote the development of T-cell leukemia. However, no studies have yet directly evaluated the impact of IL7R on T-cell oncogenesis. In the present study, we used a mouse model in which expression of an IL7R transgene is controlled by a tetracycline responsive promotor (TreIL7R rtTAhuCD2Il7r−/− mice) to analyze the role of IL7R-mediated signaling in T-cell leukemogenesis. Continuous expression of TreIL7R upon doxycycline feeding induced thymus hypertrophy and hyperplasia due to increased size and hyperproliferation of T-cells, which subsequently infiltrated lymph nodes, spleen and bone marrow, ultimately leading to leukemia/lymphoma-associated death. Adoptive transfer of thymic TreIL7R cells to immunodeficient mice confirmed their malignant origin. Surprisingly, tumors developed in recipient animals even in the absence of doxycycline administration, indicating that they eventually become independent of continuous IL7R expression. Remarkably, the tumors mimicked several features of human T-ALL. First, their immunophenotype varied considerably between animals (from CD4 CD8 double-negative to double positive to CD4 or CD8 single positive cells), reflecting the heterogeneity of human disease. Second, similar to the majority of primary T-ALL cases, most tumors displayed hyperactivation of PI3K/Akt pathway, which sometimes associated with absence or decreased PTEN protein expression. Third, the cell cycle inhibitor p27Kip1 was frequently downregulated, a molecular characteristic associated with some T-ALLs. We next sought to determine the contribution of TCR diversity to IL7R-mediated tumorigenesis by crossing mice to the F5 TCR transgenic background. Tumor development in these mice occurred with similar timing and incidence, suggesting that the tumors arise irrespectively of whether a clonal or polyclonal TCR repertoire exists. Finally, the role of Rag recombinase dependent genomic instability in tumor development was assessed by further crossing mice F5 TreIL-7R rtTAhuCD2Il7r−/− mice to Rag1−/− background. Tumor development occurred independently of Rag1 expression, indicating a dominant role for IL7R elicited signals in tumorigenesis. Altogether, our results reveal that continuous IL7R-mediated signaling promotes T-cell tumorigenesis in vivo, providing further indication that IL7R can act as a critical T-cell oncogene. Disclosures: No relevant conflicts of interest to declare.

EZH2 Inhibitor DZNep Induces Apoptosis In Adult T-Cell Leukemia/Lymphoma Cells By BCL2 Suppression Via Regulation Of Mir-181a

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Sasaki Daisuke ◽  
Hasegawa Hiroo ◽  
Taniguchi Hiroaki ◽  
Yoshitaka Imaizumi ◽  
Uno Naoki ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Target Genes ◽  
Expression Profiles ◽  
Negative Regulator ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Microarray Analyses ◽  
Bcl2 Expression

Abstract Background Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm originating from human T-cell leukemia virus type-1 (HTLV-1) infected cells. Its clinical behavior differs among patients and is sub-classified into 4 sub-types: smoldering and chronic as indolent subtypes, and acute and lymphoma as aggressive subtypes. Prognosis for patients with the aggressive subtypes is very poor with standard chemotherapy, thus a new therapeutic approach is urgently needed. Previously, we reported that EZH2, a part of the PRC2 complex, not only methylates histone, but also serves as a recruitment platform for DNA methyltransferases that methylate the promoter regions of target genes (tumor suppressor gene and miRNAs) and is overexpressed in ATL cells. We found that ATL cell lines were sensitive to DZNep (3-deazaneplanosin A), which has been shown to deplete EZH2 expression, and their proliferation was attenuated. In the present study, we clarified which target genes and miRNAs are involved in DZNep-induced ATL cell death. Results We performed microarray analyses using the ATL cell lines KK1, SO4, LMY1, and KOB to compare their gene expression profiles between cells treated and untreated with DZNep. The results showed that BCL2 transcripts in ATL cell lines were commonly suppressed by DZNep. In accordance with those findings, quantitative PCR analysis revealed that BCL2 transcripts were suppressed in DZNep-treated as compared to untreated ATL cell lines. We also confirmed that EZH2 and BCL2 protein expressions were clearly suppressed in the ATL cell lines by DZNep. These findings indicated that DZNep suppresses BCL2 expression at the transcriptional level in ATL cells. In addition, we performed another set of microarray analyses for miRNA expression profiles using primary ATL cells obtained from ATL patients and CD4 positive T-cells from healthy volunteers. The ATL cells showed decreased expression levels of several miRNAs, such as miR-101, miR-126, and miR-181a. Importantly, miR-181a has been shown to be regulated by EZH2, while miR-181a is a candidate negative regulator of BCL2 expression. Quantification of miR-181a transcripts to determine whether miR-181a is induced by DZNep showed that miR-181a was up-regulated in ATL cells by DZNep. These results strongly support the notion that miR-181a is suppressed by EZH2 and that BCL2 expression is regulated by miR-181a in ATL cells. Together, our findings indicate a unique apoptotic pathway of BCL2 suppression via miR181a and that the EZH2 inhibitor DZNep may become a novel therapeutic agent for ATL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Use of Zidovudine and Interferon Alfa With Chemotherapy Improves Survival in Both Acute and Lymphoma Subtypes of Adult T-Cell Leukemia/Lymphoma

2011 ◽  
Vol 29 (35) ◽  
pp. 4696-4701 ◽  
Author(s):  
Andrew Hodson ◽  
Siobhan Crichton ◽  
Silvia Montoto ◽  
Naheed Mir ◽  
Estella Matutes ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Interferon Alfa ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
First Line ◽  
Adult T Cell Leukemia ◽  
First Line Therapy ◽  
Line Therapy ◽  
The Impact

Purpose Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis. Patients and Methods We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed. Results The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone. Conclusion These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.

Pretransplantation Anti-CCR4 Antibody Mogamulizumab Against Adult T-Cell Leukemia/Lymphoma Is Associated With Significantly Increased Risks of Severe and Corticosteroid-Refractory Graft-Versus-Host Disease, Nonrelapse Mortality, and Overall Mortality

2016 ◽  
Vol 34 (28) ◽  
pp. 3426-3433 ◽  
Author(s):  
Shigeo Fuji ◽  
Yoshitaka Inoue ◽  
Atae Utsunomiya ◽  
Yukiyoshi Moriuchi ◽  
Kaoru Uchimaru ◽  
...  
Keyword(s):  
Relative Risk ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Adult T Cell Leukemia ◽  
Increased Risk ◽  
The Impact

Purpose Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one important treatment option for patients with aggressive adult T-cell leukemia/lymphoma (ATLL). Mogamulizumab (anti-CCR4 monoclonal antibody; Mog) was recently approved as a treatment for ATLL in Japan. Major concerns exist about the possible adverse effects of pretransplantation Mog because Mog depletes regulatory T cells for several months. We assessed the impact of pretransplantation Mog on clinical outcomes after allo-HSCT. Patients and Methods We included 996 allo-HSCT recipients age 70 years or younger with aggressive ATLL who were given the diagnosis between 2000 and 2013 and who received intensive chemotherapy by multiple chemotherapeutic drugs as first-line therapy. Before allo-HSCT, 82 patients received Mog with a median interval of 45 days from the last Mog to allo-HSCT. Results Pretransplantation Mog was associated with an increased risk of grade 3 to 4 acute graft-versus-host disease (GVHD; relative risk, 1.80; P < .01) and refractoriness to systemic corticosteroid for acute GVHD (relative risk, 2.09; P < .01). One-year cumulative incidence of nonrelapse mortality was significantly higher in patients with pretransplantation Mog compared with those without (43.7% v 25.1%; P < .01). The probability of 1-year overall survival was also significantly inferior in patients with pretransplantation Mog compared with those without (32.3% v 49.4%; P < .01). In particular, use of Mog with intervals < 50 days to allo-HSCT was associated with a dismal clinical outcome. Conclusion Pretransplantation Mog was significantly associated with an increased risk of GVHD-related mortality, which supports the relevance of CCR4-expressing Tregs after allo-HSCT in humans. In clinical practice, Mog should be cautiously used for patients with ATLL who are eligible for allo-HSCT.

Endogenous Oncogenic Nras Mutation Initiates T-Cell Leukemia/Lymphoma In a Dose-Dependent Manner

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4183-4183
Author(s):  
Jinyong Wang ◽  
Zeyang Li ◽  
Zhongde Wang ◽  
Yangang Liu ◽  
Myung-Jeom Ryu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Nras Mutation ◽  
Low Incidence ◽  
Dose Dependent ◽  
Notch1 Mutations

Abstract Abstract 4183 The oncogenic NRAS mutations are frequently identified in myeloid diseases but rare in lymphoid diseases. They occur in 4% of acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) patients and 22% of human T-ALL cell lines. Its differential roles in myeloid versus lymphoid disease development remain unclear. Here we examine the tumorigenic potential of oncogenic Nras in T-cells using two conditional Nras G12D murine knock-in models that either hypomorphically (NrasG12D Hypo) or normally (NrasG12D Norm) expresses oncogenic Nras G12D from its endogenous locus. Mice expressing monoallelic or biallelic NrasG12D Hypo develop normally and are tumor free. However, NrasG12D Norm leads to acute T-cell leukemia/lymphoma (TAL/L) in a bone marrow transplantation model, with a low incidence (∼8%) when expressing one allele (TAL/L-het) and a complete penetrance when expressing two alleles (TAL/L-homo). TAL/L-het tumors are associated with spontaneous up-regulation of oncogenic Nras in ∼67% of animals, and tumor cells are TdT positive, suggesting that they are transformed at an immature stage. In contrast, TAL/L-homo tumors express comparable levels of Nras to control thymocytes, and tumor cells are TdT negative, suggesting that they are transformed at a more mature stage. Both TAL/L-het and TAL/L-homo tumors are oligoclonal or polyclonal. Above 70% of these tumors contain clonal Notch1 mutations and are sensitive to gamma-secretase inhibitor. These data indicate that Notch1 mutations are acquired at an early stage and play an important role in the development of TAL/L-het and TAL/L-homo tumors. Together, our results show that engdogenous oncogenic Nras mutation leads to TAL/L in a dose-dependent manner, and thus explain the low incidence of oncogenic NRAS mutations in human T-cell diseases. Disclosures: No relevant conflicts of interest to declare.

Loss of p19Arf Increases the Self-Renewal Capacity of Immature Thymocytes That Over-Express LMO2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4198-4198
Author(s):  
Louise M. Treanor ◽  
Sheng Zhou ◽  
Taihe Lu ◽  
Brian P. Sorrentino
Keyword(s):  
T Cells ◽  
T Cell ◽  
Stromal Cells ◽  
Bone Marrow Cells ◽  
The Self ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Self Renewal ◽  
Thymocyte Differentiation ◽  
Cdkn2a Locus

Abstract Abstract 4198 LMO2 is a lim-only domain transcription factor that mediates protein-protein interactions in a multimeric complex containing LDB1, E47, Tal1 and either GATA1 or GATA2. It was discovered as a result of chromosomal translocations in T-cell leukemia; where it becomes abnormally regulated by T-cell receptor elements and is involved in approximately 9% of cases. LMO2 transgenic mice develop T-cell leukemia with a latency of between 10–12 months indicating that other co-operating genetic events are required. In recent X-SCID gene therapy trials 4 patients developed T-cell leukemia due to vector–induced activation of LMO2 gene expression. Two out of the 4 patients had loss of the CDKN2A locus with another having an activating insertion in BMI1, a known repressor of the CDKN2A locus. The CDKN2A locus encodes both p19Arf and p16INK4A, and p19Arf suppression is known to increase self-renewal in a variety of different stem cell systems. Because LMO2 has been shown to promote thymocyte self-renewal (Curtis et al, Science 2010); we investigated whether Arf loss could collaborate with LMO2 in regulating self-renewal of thymocyte progenitors. We utilized OP9-DL1 stromal cells that express the Notch ligand; Delta-ligand 1 which enables differentiation of immature bone marrow cells and thymocytes into mature T-cells. When cultured on OP9-DL1 stromal cells LMO2+Arf+/+ and LMO2+Arf-/- populations had a block in progression to mature T-cells at the DN2 stage of thymocyte differentiation. These DN2 thymocytes were sorted and replated onto fresh OP9-DL1 stromal cells and analysis 7 days later showed that both populations had 99% DN2 stage thymocytes, indicating that LMO2 was inducing a complete block in thymocyte differentiation. LMO2+ Arf-/- DN2 thymocytes had 3 fold more thymocytes than the Arf+/+ population 11 days after the thymocytes had been sorted. This indicates that Arf loss may be increasing the self-renewal of the DN2 population. We next transplanted either 2×105 LMO2+ Arf-/- or 2×105 LMO2 Arf+/+ DN2 thymocytes together with 2×105 WT bone marrow cells into 2 groups of 10 WT lethally irradiated syngenic recipients. After only three weeks LMO2+ Arf-/-(n=7) cells were detected in the thymi of recipient mice. Marked cells came to represent about 18% of total thymocytes between weeks 6 to 15 post-transplant, these LMO2+ Arf-/- thymocytes were able to differentiate into mature T cell lineages in the thymus. By week 18 the LMO2+ Arf-/- cells dramatically increased to 97% of total thymocytes indicating that they maybe a preleukemic pool. In contrast, no thymic repopulation with LMO2 Arf+/+ (N=7) cells was noted. Serial transplant experiments were performed by isolating mCherry+, LMO2+ thymocytes 12 weeks post transplant. Then 2×105 LMO2+ thymocytes were transplanted into secondary Rag2-/-γc-/- recipients. After 6 weeks the thymi of 2 secondary mice were analyzed and were 100% mCherry+, LMO2+ and contained mature T-cells. These LMO2+ Arf-/- thymocytes had the capacity to be serially transplanted demonstrating that Arf loss was contributing to the self-renewal potential of these LMO2+DN2 thymocytes. Comparing our data to the published result for LMO2+Arf+/+, a 100 fold less thymocytes were transplanted in our assay potentially explaining the lack of engraftment with our LMO2+Arf+/+ cells. Furthermore we observed activation of the Arf locus when these thymocytes were transplanted in vivo, indicating that somehow these LMO2+thymocytes were inducing Arf activation at later times after transplant. p19Arf expression in thymocytes has been reported to induce p53 dependent apoptosis (Miyazaki et al, Immunity 2008). This supports the concept that Arf loss contributes to the self-renewal potential of thymocytes in and above the context of LMO2 over-expression. The combination of an increase in self-renewal induced by LMO2 and loss of the gatekeeper function of self-renewal through p19Arf loss leads to acceleration in the pathogenesis of LMO2 induced T-cell malignancies. Disclosures: No relevant conflicts of interest to declare.

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