scholarly journals Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

Blood ◽  
2020 ◽  
Vol 135 (19) ◽  
pp. 1685-1695 ◽  
Author(s):  
Renate De Smedt ◽  
Julie Morscio ◽  
Lindy Reunes ◽  
Juliette Roels ◽  
Valentina Bardelli ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Cells ◽  
Integration Site ◽  
Lymphoblastic Leukemia ◽  
Residual Tumor ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non–cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non–cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.

High-Dose Cyclophosphamide for the Treatment of Refractory T-Cell Acute Lymphoblastic Leukemia in Children

2014 ◽  
Vol 36 (5) ◽  
pp. e265-e270 ◽  
Author(s):  
Rachel Kobos ◽  
Neerav Shukla ◽  
Thomas Renaud ◽  
Susan E. Prockop ◽  
Farid Boulad ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Leukemia In Children

scholarly journals High-dose methotrexate vs. Capizzi methotrexate for the treatment of childhood T-cell acute lymphoblastic leukemia

2018 ◽  
Vol 10 ◽  
pp. 44-51 ◽  
Author(s):  
Wasil Jastaniah ◽  
Naglla Elimam ◽  
Khalid Abdalla ◽  
Aeshah A. AlAzmi ◽  
Mohammed Aseeri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

scholarly journals Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2291-2304 ◽  
Author(s):  
Diego Sánchez-Martínez ◽  
Matteo L. Baroni ◽  
Francisco Gutierrez-Agüera ◽  
Heleia Roca-Ho ◽  
Oscar Blanch-Lombarte ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Antileukemic Activity ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.

Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia

2017 ◽  
Vol 405 ◽  
pp. 73-78 ◽  
Author(s):  
Sausan A. Moharram ◽  
Kinjal Shah ◽  
Fatima Khanum ◽  
Alissa Marhäll ◽  
Mohiuddin Gazi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cdk Inhibitor ◽  
Cell Acute Lymphoblastic Leukemia

Deletion of Atm in the Hematopoetic Stem Cell As a Mouse Model for Human T Cell Acute Lymphoblastic Leukemia/Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2418-2418
Author(s):  
Lori A. Ehrlich ◽  
Katherine S. Yang-Iott ◽  
Amy DeMicco ◽  
Craig H. Bassing
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Drug Combinations ◽  
Thymic Epithelial Cells ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 2418 Acute lymphoblastic leukemia (ALL) is diagnosed in approximately 2500 children per year. Although high cure rates have been achieved for ALL, these cancers account for the highest number of non-brain tumor cancer-related deaths in children. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature TCRβ−CD4+/CD8+ T-cells that represents ∼15% of pediatric ALL diagnoses, comprises most of the therapy-resistant ALL tumors, and exhibits a high frequency of relapse. The Ataxia Telangiectasia mutated (ATM) protein kinase activates the cellular response to DNA double strand breaks (DSBs) to coordinate DNA repair with cell survival, proliferation, and differentiation. Somatic inactivating ATM mutations occur in 10–20% of T-ALL and T cell lymphoblastic lymphoma (T-LL) tumors and are associated with resistance to genotoxic chemotherapy drugs and therapy relapse, likely driven by increased genomic instability in cells lacking functional ATM. The impaired DSB response of ATM-deficient cells can be exploited to design combinations of genotoxic drugs that specifically kill these cells in vitro. However, the in vivo potential of such drug combinations to treat T-ALL have not been reported. We sought to develop a pre-clinical mouse model that could be used to test effectiveness of such drug combinations to treat T-ALLs and T-LLs with somatic ATM inactivation. Although germline ATM-deficient (Atm−/−) mice succumb by six months of age to immature CD4+/CD8+ T-cell lymphomas containing genomic instability analogous to human T-ALL tumors, we sought a more physiologic model that would avoid potential complications due to ATM-deficiency in thymic epithelial cells. Thus, we generated and characterized VavCre:Atmflox/flox mice with conditional Atm inactivation restricted to hematopoietic cell lineages. These mice contain reduced numbers of TCRβ−CD4+/CD8+, TCRβ+CD4+/CD8−, and TCRβ+CD4−/CD8+ thymocytes and of TCRβ+CD4+ and TCRb+CD8+ splenic T-cells, mirroring the phenotype of Atm−/− mice. We have found that VavCre:Atmflox/flox mice succumb at an average of 95 days (range 53–183 days) to clonal TCRβ−CD4+/CD8+ or TCRβ+CD4−/CD8+ thymic lymphomas. Evaluation of the bone marrow in a subset of these mice indicates that the lymphoma has disseminated and are classified as leukemia. Our initial cytogenetic analyses of these tumors indicate that they contain both clonal translocations involving chromosome 12 and/or chromosome 14 and deletion of one allelic copy of the haploinsufficient Bcl11b tumor suppressor gene. Hemizygous BCL11B inactivation occurs in ∼20% of human T-ALL tumors, indicating the clinical relevance of VavCre:Atmflox/flox mice as a model for human T-ALL. Our ongoing studies include complete cytogenetic and molecular characterization of VavCre:Atmflox/flox tumors and in vivo testing of chemotherapeutics targeting the Atm pathway in this mouse model of T-ALL/T-LL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of JAK1/2 and BCL2 inhibition on human T cell acute lymphoblastic leukemia in vitro and in vivo

2019 ◽  
Author(s):  
Kirsti L. Walker ◽  
Sabrina A. Kabakov ◽  
Fen Zhu ◽  
Myriam N. Bouchlaka ◽  
Sydney L Olson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Combination Treatment ◽  
Lymphoblastic Leukemia ◽  
Jurkat Cells ◽  
Human T Cell ◽  
Liquid Chromatography Tandem Mass ◽  
Cell Acute Lymphoblastic Leukemia

AbstractRelapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) is difficult to salvage especially in heavily pretreated patients, thus novel targeted agents are sorely needed. Hyperactivated JAK/STAT and BCL2 overexpression promote increased T-ALL proliferation and survival, and targeting these pathways with ruxolitinib and venetoclax may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect individually, but combination treatment synergistically reduces survival and proliferation of Jurkat and Loucy cells in vitro. Using a xenograft CXCR4+ Jurkat model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS), which expresses CXCL12, as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that neither ruxolitinib nor venetoclax can effectively cross the blood-brain barrier, limiting efficacy against CNS T-ALL. Deletion of CXCR4 on Jurkat cells by CRISPR/Cas9 results in prolonged survival and a reduction in overall and neurologic clinical scores. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis will be needed to eliminate both systemic and CNS T-ALL burden and maximize the possibility of complete remission.

scholarly journals Development of the T-ALLiPSC-based Therapeutic Cancer Vaccines for T-cell acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Zhu Li ◽  
Xuemei Chen ◽  
Luning Liu ◽  
Meiling Zhou ◽  
Guangqian Zhou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocyte ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Vaccines ◽  
Therapeutic Cancer Vaccine ◽  
Whole Cell Lysate ◽  
Cell Acute Lymphoblastic Leukemia

Abstract PurposeThe T-cell acute lymphoblastic leukemia (T-ALL) is a kind of hematological malignancy in children. Despite the significant improvement in the cure rate of T-ALL upon treatment with chemotherapy regimens, steroids, and allotransplantation there are relapses. This study focuses on the tumor-specific therapeutic vaccines derived from the induced pluripotent stem cells (iPSC) to address the issue of T-ALL recurrence.MethodsPatient-derived tumor cells were reprogrammed into the iPSCs and the RNA-seq data of the T-ALL-iPSCs and H-iPSCs were analyzed. In vitro, the whole cell lysate antigens of iPSCs were prepared to induce the dendritic cells (DC) maturation, which in turn stimulated the tumor-specific T cells to kill the T-ALL tumor cells (Jurkat, CCRF-CEM, MOLT-4).ResultsBoth T-ALL-iPSCs and H-iPSCs were highly related to the tumor-related genes. The transcriptome analysis showed the T-ALL-iPSCs to be similar to the T-ALL tumor cells. The cytotoxic T lymphocyte (CTL) stimulated by the DC-loaded T-ALL-iPSC-derived antigens showed specific cytotoxicity against the T-ALL cells in vitro.ConclusionsThe T-ALL-iPSC-based therapeutic cancer vaccine can elicit a specific anti-tumor effect on T-ALL.

Growth Factor Independent-1 (Gfi1) Is Critically Required for T-Cell Acute Lymphoblastic Leukemia (T-ALL) Tumor Initiation and Maintenance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3156-3156
Author(s):  
James D. Phelan ◽  
Cyrus Khandanpour ◽  
Shane Horman ◽  
Marie-Claude Gaudreau ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Growth Factor ◽  
Cell Lines ◽  
Tumor Regression ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Apoptotic Genes

Abstract Abstract 3156 T cell acute lymphoblastic leukemia (T-ALL) is one of the most common childhood cancers associated with mutations in NOTCH1. The Growth factor independent-1 (Gfi1) transcriptional repressor gene was originally discovered as a common target of Moloney murine leukemia virus (MMLV) proviral insertion in murine T-ALL. In fact, the Gfi1 locus is the most frequently activated gene in MMLV-induced T cell leukemia. Therefore, we investigated whether the most commonly activated gene in MMLV-induced murine T-ALL, Gfi1, could collaborate with the most commonly activated gene in human T-ALL, NOTCH1. Here, we show that GFI1 expression is associated with Notch signaling in human T-ALL (p'0.0003). Functionally, Gfi1 collaborates with Notch-induced murine T-ALL by accelerating an already rapid disease model (p=0.03) without altering the lymphoblastic nature of the disease. Furthermore, inducible deletion of Gfi1 is counter-selected in both Notch-driven retroviral and transgenic mouse models of T-ALL; whereas, constitutive absence of Gfi1 completely prevents transgenic Notch-induced T-ALL (p≤0.04). However, T-ALL tumors can form in Gfi1-/- animals using either ENU-mutagenesis or MMLV-infection, yet tumor formation is delayed (p≤0.02, p≤0.03 respectively). This suggests that Gfi1 deletion does not prevent the formation of the T-ALL initiating cell and that Gfi1 might be absolutely required for Notch-induced T-ALL. Most striking is that Gfi1 is required for T-ALL maintenance in vitro and in vivo. Using three separate Tal1-initiated murine T-ALL cell lines, the overexpression of the Gfi1 dominant-negative, Gfi1N382S, was quickly and completely counter-selected. As Gfi1 has previously been found to regulate pro-apoptotic genes in T cells, we attempted to rescue the above loss of function phenotype by overexpressing the anti-apoptotic factor Bcl2. Notably, counter-selection of Gfi1N382 is not observed or is significantly delayed in all three cell lines. In vivo, inducible deletion of Gfi1 leads to both mutagen- or Notch-induced tumor regression as measured by ultrasound. In fact, levels of Gfi1 expression directly correlate to tumor regression and disease free survival of T-ALL. Finally, targeting Gfi1 enhances the efficacy of radiation therapy and bone marrow transplantation. Deletion of Gfi1 sensitizes T-ALL tumors and T cells to p53-dependent apoptosis after exposure to DNA-damaging agents such as radiation, Etoposide or Daunorubicin by de-repression of the pro-apoptotic Gfi1 target gene Bax. These data extend the role of Gfi1 to human T-ALL and suggest that T-ALL is dependent upon Gfi1 to repress pro-apoptotic genes for tumor survival, ultimately highlighting a new therapeutic target in the fight against lymphoid malignancies. Disclosures: No relevant conflicts of interest to declare.

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