-
British Journal of Haematology Jun 2019Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority,... (Review)
Review
Lymphoblastic lymphoma (LBL) is the second most common type of Non-Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25-35% of all cases. The majority, 70-80%, is of T-lymphoblastic origin while 20-25% arise from B lymphoblasts. With current therapy, the event-free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T-LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.
Topics: Adolescent; Child; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Neoplasm Staging; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Symptom Assessment; Treatment Outcome
PubMed: 30809797
DOI: 10.1111/bjh.15793 -
Blood Advances Jan 2024T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (T-ALL/LBL) is a rare hematologic malignancy most commonly affecting adolescent and young adult males.... (Review)
Review
T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma (T-ALL/LBL) is a rare hematologic malignancy most commonly affecting adolescent and young adult males. Outcomes are dismal for patients who relapse, thus, improvement in treatment is needed. Nelarabine, a prodrug of the deoxyguanosine analog 9-β-arabinofuranosylguanine, is uniquely toxic to T lymphoblasts, compared with B lymphoblasts and normal lymphocytes, and has been developed for the treatment of T-ALL/LBL. Based on phase 1 and 2 trials in children and adults, single-agent nelarabine is approved for treatment of patients with relapsed or refractory T-ALL/LBL, with the major adverse effect being central and peripheral neurotoxicity. Since its approval in 2005, nelarabine has been studied in combination with other chemotherapy agents for relapsed disease and is also being studied as a component of initial treatment in pediatric and adult patients. Here, we review current data on nelarabine and present our approach to the use of nelarabine in the treatment of patients with T-ALL/LBL.
Topics: Male; Adolescent; Young Adult; Humans; Child; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; Recurrence; Lymphoma, T-Cell; T-Lymphocytes
PubMed: 37389830
DOI: 10.1182/bloodadvances.2023010303 -
Nature Medicine Apr 2022KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell... (Meta-Analysis)
Meta-Analysis
KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.
Topics: Bone Marrow; Child; Gene Rearrangement; Humans; Infant; Mutation; Myeloid-Lymphoid Leukemia Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transcriptome
PubMed: 35288693
DOI: 10.1038/s41591-022-01720-7 -
Neuroimmunomodulation 2024T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is... (Review)
Review
BACKGROUND
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is generally thought to originate in the thymus since lymphoblasts express phenotypic markers comparable to those described in thymocytes in distinct stages of development. Although around 50% of T-ALL patients present a thymic mass, T-ALL is characterized by peripheral blood and bone marrow involvement, and central nervous system (CNS) infiltration is one of the most severe complications of the disease.
SUMMARY
The CNS invasion is related to the expression of specific adhesion molecules and receptors commonly expressed in developing T cells, such as L-selectin, CD44, integrins, and chemokine receptors. Furthermore, T-ALL blasts also express neurotransmitters, neuropeptides, and cognate receptors that are usually present in the CNS and can affect both the brain and thymus, participating in the crosstalk between the organs.
KEY MESSAGES
This review discusses how the thymus-brain connections, mediated by innervation and common molecules and receptors, can impact the development and migration of T-ALL blasts, including CNS infiltration.
Topics: Humans; Thymus Gland; Brain; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Animals
PubMed: 38272012
DOI: 10.1159/000536419 -
Frontiers in Molecular Neuroscience 2023TDP-43 proteinopathy in Alzheimer's disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in...
INTRODUCTION
TDP-43 proteinopathy in Alzheimer's disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.
METHODOLOGY
We have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.
RESULTS
TDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.
CONCLUSION
TTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease.
PubMed: 37621404
DOI: 10.3389/fnmol.2023.1243277 -
Molecular Psychiatry Jun 2021While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not...
Potential depression and antidepressant-response biomarkers in human lymphoblast cell lines from treatment-responsive and treatment-resistant subjects: roles of SSRIs and omega-3 polyunsaturated fatty acids.
While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines, and elements of the cAMP-generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while lymphoblasts show paradoxical responses to neurons and glia, patient-derived lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
Topics: Antidepressive Agents; Biomarkers; Cell Line; Depression; Fatty Acids, Omega-3; Humans; Selective Serotonin Reuptake Inhibitors
PubMed: 32327735
DOI: 10.1038/s41380-020-0724-6 -
Mediterranean Journal of Hematology and... 2014Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly between ALL subsets, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT) and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review summarizes how best to identify ALL and the most relevant ALL subsets.
PubMed: 25408859
DOI: 10.4084/MJHID.2014.073 -
Experimental Hematology Aug 2015T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia... (Review)
Review
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable acute and long-term side effects, about 15% of pediatric and 40% of adult T-ALL patients still relapse, owing to acquired therapy resistance, and present with very dismal survival perspectives. Unfortunately, the molecular mechanisms by which residual T-ALL tumor cells survive chemotherapy and act as a reservoir for leukemic progression and hematologic relapse remain poorly understood. Nevertheless, it is expected that enhanced molecular understanding of T-ALL disease biology will ultimately facilitate a targeted therapy driven approach that can reduce chemotherapy-associated toxicities and improve survival of refractory T-ALL patients through personalized salvage therapy. In this review, we summarize recent biological insights into the molecular pathogenesis of T-ALL and speculate how the genetic landscape of T-ALL could trigger the development of novel therapeutic strategies for the treatment of human T-ALL.
Topics: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Cellular Reprogramming; Child; Child, Preschool; Epigenesis, Genetic; Hematopoietic Stem Cell Transplantation; Humans; Infant; Precursor Cells, T-Lymphoid; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 26123366
DOI: 10.1016/j.exphem.2015.05.017 -
Blood Mar 2017T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors.... (Review)
Review
T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation in T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers promoting cell anabolism and cell cycle progression. Oncogenic NOTCH signaling, which is activated in more than 65% of T-ALL patients by activating mutations in the gene, has emerged as a major regulator of leukemia cell growth and metabolism. T-ALL mutations result in ligand-independent and sustained NOTCH1-receptor signaling, which translates into activation of a broad transcriptional program dominated by upregulation of genes involved in anabolic pathways. Among these, the oncogene plays a major role in NOTCH1-induced transformation. As result, the oncogenic activity of NOTCH1 in T-ALL is strictly dependent on MYC upregulation, which makes the NOTCH1-MYC regulatory circuit an attractive therapeutic target for the treatment of T-ALL.
Topics: Cell Transformation, Neoplastic; Humans; Mutation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-myc; Receptor, Notch1
PubMed: 28115368
DOI: 10.1182/blood-2016-09-692582