T-Cell Prolymphocytic Leukemia with Extensive Cardiovascular Infiltrate Leading to Multiple Myocardial Infarctions and Cardiac Death

Lymphocytic neoplasm involving the heart is not common and usually presents with pericardial effusion or focal myocardial infiltration. Myocardial infarctions due to leukemic infiltration of the coronary arteries are rarely reported. We present the case of a 52-year-old Guatemalan man with a one-year history of untreated T-cell prolymphocytic leukemia. He was admitted to our hospital for chemotherapy and evaluation of a pulmonary cavitary lesion by wedge resection. During sedation, the patient experienced acute respiratory failure and hypovolemic shock, from which he could not be resuscitated. Autopsy revealed that leukemic cells extensively infiltrated the aorta, myocardium, and coronary arteries. The lumina of the 3 major coronary artery branches showed 70% to 95% stenosis, with multifocal remote myocardial infarctions. Tumor cells were also detected in the lungs and other organs. The acute cardiorespiratory insufficiency secondary to leukemia—particularly the extensive infiltration of the coronary arteries and myocardium, and the multiple myocardial infarctions—eventually resulted in cardiac death.

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Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses

Blood ◽

10.1182/blood.v67.4.949.949 ◽

1986 ◽

Vol 67 (4) ◽

pp. 949-956 ◽

Cited By ~ 23

Author(s):

CC Sohn ◽

DW Blayney ◽

JL Misset ◽

G Mathe ◽

G Flandrin ◽

...

Keyword(s):

T Cell ◽

Hairy Cell Leukemia ◽

Sheep Erythrocyte ◽

The Other ◽

Leukemic Cells ◽

Type I ◽

T Cell Leukemia ◽

Hairy Cell ◽

Cell Leukemia ◽

Prolymphocytic Leukemia

Abstract We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

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Complete Cytogenetic Response in a Case of T-PLL with a Complex Karyotype after Treatment with Alemtuzumab.

Blood ◽

10.1182/blood.v106.11.4535.4535 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4535-4535

Author(s):

André F. Marinato ◽

Fábio Morato de Oliveira ◽

Rafael H. Jácomo ◽

Edgar G. Rizzatti ◽

Roberto P. Falcão ◽

...

Keyword(s):

T Cell ◽

Lymph Nodes ◽

Peripheral Blood ◽

Leukemic Cells ◽

Terminal Deoxynucleotidyl Transferase ◽

Cell Phenotype ◽

Complex Karyotype ◽

Prolymphocytic Leukemia ◽

Human T Cell ◽

Cytogenetic Remission

Abstract T-prolymphocytic leukemia (T-PLL) is an aggressive T-cell leukemia characterized by the proliferation of prolymphocytes with a mature postthymic T-cell phenotype and commonly involves the blood, bone marrow, lymph nodes, liver, spleen, and skin. Leukemic cells appear as small to medium-sized prolymphocytes or small variant cells, occasionally with cerebriform nuclei. T prolymphocytes are CD2+, CD3+, and CD7+ and may express CD4+CD8−, CD4+CD8+, or CD4−CD8+ markers. The most frequent chromosomal abnormalities are t(14;14)(q11;q32), inv(14)(q11q32), t(X;14)(q28;q11), i(8)(q10), and t(8;8)(p12;q11). Although patients treated with conventional chemotherapy generally have a poor prognosis, alemtuzumab (Campath®) has been associated with good clinical responses in patients with T-PLL. Routine cytogenetic analysis to determine the response to alemtuzumab has not been performed in patients with T-PLL. This study reports the complete cytogenetic remission achieved following alemtuzumab treatment in a single patient with T-PLL. The 41-year old male patient presented with weight loss, night sweats, diffuse lymphadenopathy and hepatosplenomegaly, in the absence of any skin rash. Peripheral blood counts were: platelets 128 x 109/L and leukocytes 93.6 x 109/L, and hemoglobin values were 12.5 g/dL. The lymphocytes were mostly medium-sized with round to irregular nuclei; some cerebriform cells were also observed, with intermediate chromatin, single evident nucleoli, and a basophilic cytoplasm. Human T-cell lymphotrophic virus-1 serology was negative. Immunophenotypic studies showed CD2+, CD3+, CD5+, CD7+, CD4−, CD8+, CD1−, terminal deoxynucleotidyl transferase-negative (TdT-), and T-cell receptor a/b+. Classic cytogenetics and spectral karyotyping (SKY) were performed and an abnormal karyotype was observed in 18 metaphases analyzed: 46, t(X;14)(q28;q11), t(Y;14)(q12;q11), r[i(8)(q10)]. These abnormalities have not been previously reported in cases of T-PLL. The patient then underwent chemotherapy with CHOP, and subsequent therapy with fludarabine. The patient was then treated with alemtuzumab, 30 mg twice a week, for a total of 7 doses. The patient achieved complete clinical, hematological, and cytogenetic remission, characterized by lack of symptoms, reduction of lymph nodes, liver, and spleen size to normal volumes, and the disappearance of prolymphocytes from peripheral blood. Cytogenetic studies performed 7 months after treatment by classic cytogenetics and SKY revealed a karyotype of 46,XY[20]. This study is the first to demonstrate a complete cytogenetic remission following treatment with alemtuzumab in a patient with T-PLL that was refractory to standard chemotherapy. This is especially impressive in a patient with a complex karyotype and with different cytogenetic alterations not previously described.

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Analysis of In Vitro Effects of Bortezomib (Velcade) on T Cell Prolymphocytic Leukemia (T-PLL).

Blood ◽

10.1182/blood.v108.11.4426.4426 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4426-4426

Author(s):

Fulya Ozpuyan ◽

Paul N. Meyer ◽

Hytham Al-Masri ◽

Hongyu Ni ◽

Serhan Alkan

Keyword(s):

T Cell ◽

Lymphoproliferative Disorder ◽

Flow Cytometric Analysis ◽

Leukemic Cells ◽

Cell Phenotype ◽

Base Line ◽

Prolymphocytic Leukemia ◽

Bortezomib Treatment ◽

Flow Cytometric

Abstract T-cell prolymphocytic leukemia (T-PLL) is an aggressive lymphoproliferative disorder with postthymic T cell phenotype and prolymphocytic morphology. In the majority of patients, the leukemic process progresses rapidly and patients die shortly after diagnosis (median survival of 7 months). Bortezomib, the first proteasome inhibitor to be approved for use in haematological malignancies such as multiple myeloma, is beginning to be utilized as an effective anti-neoplastic agent in other hematopoietic and non-hematopoietic neoplastic disorders. We report here the in vitro apoptotic effects of bortezomib on leukemic cells isolated from three T-PLL patients. Interestingly, one of the patient’s leukemia developed in the setting of immunosupression due to transplant therapy (post-transplant lymphoproliferative disorder). Flow cytometric analysis of leukemic cells of the three patients showed CD8, double CD4+CD8+ and double CD4−CD8− immunophenotypic features. All cases showed monoclonal band pattern by T-cell receptor (TCR) gene rearrangement as analyzed by the PCR amplification of the TCR gamma heavy chain gene. Freshly isolated leukemic cells with the CD8 phenotype T-PLL analyzed for apoptosis after ficoll hypaque separation and cultured in the presence of various concentration of Bortezomib (0.001, 0.01, 0.1, 1, and 10 uM) for dose curve analysis. Apoptosis of the leukemic cells was determined by Annexin-V and 7-AAD staining and flow cytometric analysis after incubation at 24 and 72 hours, respectively. Samples treated for 72 hours showed higher rate of apoptosis compared to 24 hours: 10 uM (62% increase above the base line of control cells), 1 uM (58%), 0.1 uM (55%), 0.01 uM (40%) and 0.001 uM (0%) concentrations while samples treated for 24 hours with 10 uM showed (42% increase above the base line of control cells) and 1 uM (33% increase above the base line). Light microscopic analysis of leukemic cells treated with Bortezomib confirmed that the majority of cells undergo apoptosis with Bortezomib treatment as it revealed nuclear fragmentation and apoptotic bodies. Leukemic cells recovered from cryopreservation from the second and third T-PLL patient samples analyzed also showed significant increase in early and late apoptosis at 24 hours with Bortezomib treatment (10nm). These results suggest that Bortezomib may provide an alternate therapy in the treatment of T-PLL. Future collaborative efforts investigating efficacy with Bortezomib as a single agent or in combination with other therapeutic agents will be crucial to improving survival for patients with this disease.

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Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses

Blood ◽

10.1182/blood.v67.4.949.bloodjournal674949 ◽

1986 ◽

Vol 67 (4) ◽

pp. 949-956

Author(s):

CC Sohn ◽

DW Blayney ◽

JL Misset ◽

G Mathe ◽

G Flandrin ◽

...

Keyword(s):

T Cell ◽

Hairy Cell Leukemia ◽

Sheep Erythrocyte ◽

The Other ◽

Leukemic Cells ◽

Type I ◽

T Cell Leukemia ◽

Hairy Cell ◽

Cell Leukemia ◽

Prolymphocytic Leukemia

We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

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Intra-Lineage Phenotypic Switch in T-Cell Prolymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.2005.2005 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2005-2005

Author(s):

Nnenna Osuji ◽

Ilaria Del Giudice ◽

Estella Matutes ◽

Vasantha Brito-Babapulle ◽

Alison Morilla ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Clinical Features ◽

Residual Disease ◽

Leukemic Cells ◽

Phenotypic Change ◽

Phenotypic Switch ◽

Acute Leukemias ◽

Prolymphocytic Leukemia ◽

Cytogenetic Abnormalities

Abstract T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell disorder characterized by an aggressive clinical course and short survival. Immunophenotypically, the leukemic cells show heterogeneous CD4 and CD8 expression; most cases are CD4+CD8− but, CD4+CD8+ and CD4−CD8+ cases are recognized. CD4+CD8+ phenotype is conventionally associated with cortical thymocytes, however, double positive T-prolymphocytes, are TdT −, CD1a − and CD3+ suggesting a post-thymic origin. Phenotypic changes in malignant cells while recognized in acute leukemias, are rare in mature T-cell disorders. In T-PLL, there is only 1 report describing 2 cases of phenotypic change (Tuset et al, Leukemia and Lymphoma 2001.42:1379-83). We retrospectively investigate the frequency of this phenomenon amongst 20 patients with T-PLL for whom sequential immunophenotyping of leukemic cells was available. This included the 2 cases previously reported. Diagnosis of T-PLL was based on clinical features, morphology, immunophenotype and karyotype. Membrane markers were sequentially evaluated by flow cytometry on peripheral blood and bone marrow. Sequential chromosome analysis of metaphases derived from T-mitogen stimulated metaphases cultures was available in a proportion of cases. Intra-lineage phenotypic switch occurred at relapse in 5 cases (25%) (table 1). No characteristic pattern of switch was seen. Serial karyoptying was available in 3 of these 5 patients (60%) and showed acquisition of additional cytogenetic abnormalities at the time of relapse. Change in morphology was documented in 1 case where cells displayed a more ‘blastic’ appearance with loss of CD52. Change in phenotype was mirrored in clinical features with increasingly progressive disease and refractoriness to treatment. In all cases, a mature TdT negative phenotype was maintained. Splenectomy was not performed in the interval between initial and documented change in phenotype and LGL’s were not apparent morphologically or by flow cytometry in these 5 patients Change in phenotype in T-PLL Subsequent phenotype Initial phenotype CD4+CD8− CD4+CD8+ CD4−CD8+ Total * change in phenotype CD4+CD8− 8 1* 0 9 (45%) CD4+CD8+ 0 2 2* 4 (20%) CD4−CD8+ 1* 1* 5 7 (35%) Total 9 (45%) 4 (20%) 7 (35%) 20 . All patients received alemtuzumab treatment and while it is possible that this agent selectively depleted sub-clones of the disease, the lack of a consistent emergent phenotype, together with acquisition of additional cytogenetic abnormalities as opposed to replacement by a different abnormal karyotype, favors clonal evolution as a likely cause. Such change in phenotype was not observed in the remaining 15 patients despite alemtuzumab treatment in the majority. Our findings indicate that intra-lineage phenotypic switch in T-PLL occurs in up to 25% of cases. This indicates the need to use comprehensive T-cell panels in monitoring for minimal residual disease and/or relapse. Sequential evaluation of phenotype and cytogenetics may provide valuable insights into mechanisms of relapse and resistance and may impact on treatment selection in T-PLL.

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Noncanonical effector functions of the T-memory–like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Blood ◽

10.1182/blood.2019003348 ◽

2020 ◽

Vol 136 (24) ◽

pp. 2786-2802 ◽

Cited By ~ 1

Author(s):

S. Oberbeck ◽

A. Schrader ◽

K. Warner ◽

D. Jungherz ◽

G. Crispatzu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Expression Profiles ◽

Leukemic Cell ◽

Leukemic Cells ◽

Transcriptional Responses ◽

Prolymphocytic Leukemia ◽

Effector Functions ◽

Activated State ◽

Memory Type

Abstract T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

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CCR7 as a novel therapeutic target in t-cell PROLYMPHOCYTIC leukemia

Biomarker Research ◽

10.1186/s40364-020-00234-z ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Carlos Cuesta-Mateos ◽

Patricia Fuentes ◽

Alexandra Schrader ◽

Raquel Juárez-Sánchez ◽

Javier Loscertales ◽

...

Keyword(s):

T Cell ◽

Leukemic Cells ◽

Prolymphocytic Leukemia ◽

Medical Need ◽

Wide Range ◽

Xenograft Models ◽

New Compounds ◽

Anti Tumor Activity ◽

Functional Receptor

Abstract T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.

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Novel Phenotypic and Genetic Analysis of T-Cell Prolymphocytic Leukemia (T-PLL)

Blood ◽

10.1182/blood.v124.21.1682.1682 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1682-1682 ◽

Cited By ~ 1

Author(s):

Henan Zhang ◽

Esteban Braggio ◽

Jaime Davila ◽

Andrew L. Feldman ◽

Timothy G. Call ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Rna Sequencing ◽

Flow Cytometric Analysis ◽

T Cell Subsets ◽

Leukemic Cells ◽

Akt Inhibitor ◽

Prolymphocytic Leukemia ◽

Flow Cytometric ◽

Whole Exome

Abstract Introduction T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-Cell malignancy typically associated with aggressive clinical course. Leukemic T-cells demonstrate post-thymic T-cell phenotypes (Tdt-, CD1a-, CD5+, CD2+ and CD7+) and commonly are CD4+/CD8- T-cells, but co-expression of CD4+/CD8+ or CD8+/CD4- have also been observed. Rearrangement of chromosome 14 involving TCL1 locus is the cornerstone for T-PLL diagnosis which leads to overexpression of oncogene TCL1. As a binding partner for TCL1, AKT expression correlates with worse prognosis. Despite advances in identification of novel mutations, therapeutic option is limited with most patients having very short survival. Herein, we performed a detailed analysis of specific T-cell subsets affected in T-PLL and a comprehensive genomic analysis by whole exome sequencing (WES) and RNA sequencing. We also explored the preclinical efficacy of targeting AKT activation by AKT inhibitor MK2206 on leukemic T-cells isolated from T-PLL patients. Methods T-PLL leukemic cells were isolated from blood or marrow samples of T-PLL patients (n=9) and were tested for involved T-cell subsets by multicolor flow cytometric analysis. Leukemic T-cells were treated with escalating doses of MK2206 (0 to 10 µM) for about 80 hours and were assessed for their apoptosis levels using Annexin V flow cytometric analysis. Whole exome sequencing (WES) and RNA sequencing were conducted using genomic DNA and RNA isolated from purified leukemic T cells from T-PLL patients. Results Phenotypic analysis of T-cell subsets in T-PLL patients showed that leukemic T-cells in 4 untreated T-PLL patients are consistent with naïve T-cell phenotype (CD45RA+, CD45RO-, CCR7+). Leukemic T-cells in 3 of the untreated patients and in 2 of the treated patients have central memory T (CD45RA-, CD45RO+, CCR7+) and effector memory T phenotypes (CD45RA-, CD45RO+,CCR7-) respectively. MK2206 treatment was able to induce dose-dependent apoptosis on the isolated PBMC (containing > 90% leukemic T-cells) of T-PLL patients (n=4) (IC50: 5 µM). FISH analysis found a rearrangement of TCL1 locus on chromosome 14 in all T-PLL cases (n=9). Three cases have also been detected to have del (11q) involving ATM locus and one patient has both del(11q) and del(17p). Subsequent WES (n=7) and RNA sequencing (n=6) analysis revealed recently reported mutations in ATM (frame shift mutation and early stop mutation W579*) in 2 cases, JAK3 (M511I) in 2 cases and STAT5B (T628S and N642H) in 2 cases. Importantly, novel somatic mutations in gene IKZF1 (N159S), NTRK1 (R33W), AP2A2 (P514L), HDAC8 (I115R), RARB (G90W) and TNIP2 (K104Q) were detected by WES. Mutations in EML4 (L548W and F304S) and VAV3 (C282Y and splice site mutation) were also identified in 2 different T-PLL cases. RNA sequencing revealed several fusion transcripts resulting in early stop of several different genes including PTPRT, L3MBTL1, UCKL1 in one T-PLL case. Conclusion T-PLL leukemic T-cells are consistent with either naïve or central memory T-cell subsets in untreated patients. The AKT inhibitor MK-2206 was capable of inducing apoptosis and could be a potential therapeutic agent for T-PLL patients. In addition, we detected known mutations in ATM and JAK-STAT pathways. Novel mutations in genes involving DNA binding and chromatin remodeling (IKZF1, HDAC8) or kinase signal pathway (NTRK1, TNIP2, VAV3, EML4) were uncovered. These results suggest that further therapeutic approaches could be developed to target DNA binding factors or JAK-STAT or AKT-TCL1 signal pathway with an ultimate goal to improve survival of T-PLL patients. Disclosures Off Label Use: Off label use of MK2206: MK-2206 is an AKT inhibitor obtained from Selleck Chemicals and is used to treat leukemic cells in vitro to test the leukemic sensitivity to AKT inhibition. .

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Inhibition of Proliferation and Induction of Apoptosis by Thymoquinone via Modulation of TGF Family, p53, p21 and Bcl-2α in Leukemic Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170912133054 ◽

2018 ◽

Vol 18 (2) ◽

pp. 210-215 ◽

Cited By ~ 3

Author(s):

Mona Diab-Assaf ◽

Josiane Semaan ◽

Marwan El-Sabban ◽

Soad K. Al Jaouni ◽

Rania Azar ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

T Cell ◽

Flow Cytometric Analysis ◽

Leukemic Cells ◽

Cell Cycle Distribution ◽

Dependent Manner ◽

Apoptosis Induction ◽

Inhibition Of Proliferation ◽

Human T Cell

Introduction: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. Objective: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and Methods: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL.

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