Management of adults with T-cell lymphoblastic leukemia

Marks, David I.; Rowntree, Clare

doi:10.1182/blood-2016-07-692608

Cited by 134 publications

(117 citation statements)

References 90 publications

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“…[19][20][21] Intensive chemotherapy and/or allogeneic hematopoietic stem cell transplant often do not prevent treatment-refractory relapse; for these patients, and those with other high-risk features, such as adult age, there is a dearth of treatment options. 19,[22][23][24][25] A major obstacle to the development of effective CAR T cells for T-cell malignancies is that the surface marker profile of malignant T cells (which generally lack CD19 or CD22 expression) largely overlaps that of activated T lymphocytes. 19,26 CARs directed against such targets are likely to lead to the self-elimination of the CAR T cells.…”

Section: Introductionmentioning

confidence: 99%

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

et al. 2017

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“…(1) Cure rates, respectively, reach 60% in adults and over 80% in pediatric patients when treated with combination chemotherapy protocols. (2)(3)(4) However, resistance to first-line therapy is seen in 25% of children and more than 50% of adults, and the cohort that do respond to current ALL chemotherapy protocols often suffer from both acute and chronic toxic side-effects despite treatment success. (5) Therefore, there is a need for the development of novel, non-chemotherapeutic treatments for T-ALL.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

Walker

Kabakov

Zhu

et al. 2019

Preprint

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Relapsed/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 dosedependent 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 ontarget 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.

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“…Conventional therapy leads to complete remission in only 10–15% of patients. T-ALL, which accounts for 25% of cases of adult ALL, is characterized by the malignant clonal expansion of immature T-cell progenitors (14). These are aggressive malignancies that do not respond well to chemotherapy and have a poorer prognosis than their B cell counterparts.…”

Section: Introductionmentioning

confidence: 99%

Silencing of LSD1 gene modulates histone methylation and acetylation and induces the apoptosis of JeKo-1 and MOLT-4 cells

Zou

Huang

Zou

et al. 2017

International Journal of Molecular Medicine

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Lysine-specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics; however, the pathological roles of its dysfunction in mantle cell lymphoma (MCL) and T-cell acute lymphoblastic leukemia remain to be elucidated. In this study, we evaluated LSD1, and histone H3 lysine 4 (H3K4)me1 and H3K4me2 expression in patients with MCL and silenced LSD1 in JeKo-1 and MOLT-4 cells, in order to define its role in JeKo-1 and MOLT-4 cell proliferation and apoptosis. We retrospectively analyzed the protein expression of LSD1, and mono- and dimethylated H3K4 (H3K4me1 and H3K4me2), and cyclin D1 and Ki67 in 30 cases of MCL by immunohistochemistry. The correlation of LSD1, H3K4me1 and H3K4me2 with Ki67 was determined by statistical analysis. LSD1 was silenced by small interfering RNA (siRNA). Cell apoptosis and cell proliferation were detected by flow cytometry and 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression levels of LSD1, histone methylated H3K4, histone acetylated H3, cyclin D1, apoptotic proteins, p15 and DNA methyltransferase 1 (DNMT1) were examined by western blot analysis. We demonstrated that LSD1 was upregulated, and that H3K4me1 and H3K4me2 were downregulated in the cases with MCL, compared to those with proliferative lymphadenitis (p<0.05). LSD1 positively correlated with Ki67 in MCL [Cohen's kappa (κ)=0.667, p<0.01]. There was no significant correlation between H3K4me1 and H3K4me2, and Ki67 (κ=−0.182, p>0.05, κ=−0.200, p>0.05). The silencing of LSD1 decreased the levels of the apoptosis-related proteins, Bcl-2, pro-caspase-3 and C-myc, and decreased those of DNMT1 and increased p15, and resulted in the loss of cell viability and the induction apoptosis. The silencing of LSD1 increased the expression of H3K4me1 and H3K4me2, and histone acetylated H3 in the JeKo-1 and MOLT-4 cells. LSD1 siRNA also decreased cyclin D1 expression in the JeKo-1 cells. On the whole, our findings demonstrate that the overexpression of LSD1 may be associated with the pathogenesis in MCL. We demonstrated that the silencing of LSD1 is capable of removing the mono- and dimethyl groups from H3K4, and upregulating the histone acetylation of H3 in JeKo-1 and MOLT-4 cells. The silencing of LSD1 inhibited cell growth and induced cell apoptosis. Of note, in JeKo-1 cells, the silencing of LSD1 decreased cyclin D1 expression, which is one of the genes that contribute to the pathogenesis of MCL. LSD1 may thus be a possible therapeutic target in MCL and acute lymphoblastic leukemia MOLT-4 cells.

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Management of adults with T-cell lymphoblastic leukemia

Cited by 134 publications

References 90 publications

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

Silencing of LSD1 gene modulates histone methylation and acetylation and induces the apoptosis of JeKo-1 and MOLT-4 cells

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