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Human Pathology Jun 2024The histopathological diagnosis of T-lymphoblastic leukemia/lymphoma, NOS (T-ALL), is based on morphology and positivity for CD3 and TdT. Early T-precursor lymphoblastic...
Clinicopathological differences between T-lymphoblastic leukemia/lymphoma, early T-precursor lymphoblastic leukemia/lymphoma, and mixed-phenotype acute leukemia with T lineage: an analysis of 41 adult cases.
The histopathological diagnosis of T-lymphoblastic leukemia/lymphoma, NOS (T-ALL), is based on morphology and positivity for CD3 and TdT. Early T-precursor lymphoblastic leukemia/lymphoma (ETP-ALL) and mixed-phenotype acute leukemia (MPAL), T/M, and/or B rarely occur and are usually diagnosed using flow cytometry. Using only formalin-fixed paraffin-embedded tissue raises the risk of misdiagnosis due to underestimation. Immunostaining markers for T cell (CD1a, CD4, CD5, CD8), B cell (CD19, CD10, CD22, CD79a), and stem/myeloid-related cell (CD33, CD34, CD117, MPO, lysozyme) diagnosed 25 T-ALL cases (61%), 7 MPAL (17%), 6 ETP-ALL (15%), and 3 near ETP-ALL (7%), with subsequent analysis of their clinicopathological characteristics. Patients with MPAL had significantly poorer 2-year progression-free survival (14.3% vs. 60.4%, P = 0.012) and 5-year overall survival (28.6% vs. 65.9%, P = 0.011) than did those with T-ALL, whereas ETP-ALL and near ETP-ALL did not. Of the seven patients with MPAL, three were classified as T/B, two as T/M, and two as T/M/B. Because most MPALs (6/7) share the ETP-ALL phenotype, immunohistochemistry for CD19 and MPO should be performed to avoid misdiagnosing MPAL as ETP-ALL. All three patients with TdT-negative MPAL died of the disease. Four patients with MPO-positive MPAL relapsed during the early phase (1-9 months). Five patients received the ALL regimen, but two patients received acute myeloid leukemia and lymphoma regimens, respectively. In this study, MPAL exhibited a poorer prognosis compared to T-ALL, unlike ETP-ALL. Thus, immunohistochemical classification with multiple antibody panels is useful for accurate diagnosis and treatment.
PubMed: 38945375
DOI: 10.1016/j.humpath.2024.06.016 -
In Vivo (Athens, Greece) 2024Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix...
BACKGROUND/AIM
Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP.
PATIENTS AND METHODS
A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity.
RESULTS
All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity.
CONCLUSION
The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.
Topics: Humans; Child; Mercaptopurine; Female; Male; Pyrophosphatases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Child, Preschool; Indonesia; Adolescent; Genotype; Infant; Polymorphism, Single Nucleotide; Alleles; Gene Frequency; Genetic Predisposition to Disease; Antimetabolites, Antineoplastic; Polymorphism, Genetic; Nudix Hydrolases
PubMed: 38936894
DOI: 10.21873/invivo.13662 -
In Vivo (Athens, Greece) 2024To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination...
BACKGROUND/AIM
To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination therapies including a selective BCL-2 inhibitor for T-ALL cell lines, namely Jurkat, CCRF-CEM, and Loucy.
MATERIALS AND METHODS
Loucy is an early T-precursor ALL (ETP-ALL) cell line characterized by an immature phenotype, whereas Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Monotherapy was conducted with venetoclax, cytarabine, bendamustine, or azacytidine, whereas combination therapy was performed with venetoclax plus cytarabine, venetoclax plus bendamustine, or venetoclax plus azacytidine. Cell viability assay was conducted after 48 h using Trypan blue and the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Statistical analysis for evaluating synergistic interactions between anticancer drugs was performed by using the SynergyFinder Plus and drc R package.
RESULTS
Adding venetoclax to cytarabine, bendamustine, or azacitidine achieved an additive effect, with Loewe synergic scores ranging from -10 to 10 in Jurkat and CCRF-CEM. Conversely, the combination of venetoclax and cytarabine displayed an additive effect (Loewe synergic score: 8.45 and 5.82 with MTS and Trypan blue assays, respectively), whereas venetoclax plus bendamustine or azacitidine exhibited a synergistic effect (Loewe synergic score >10 with MTS assay) in Loucy. Remarkably, the Bliss/Loewe score revealed that the combination of venetoclax and bendamustine was the most synergistic, yielding a score of 13.832±0.55.
CONCLUSION
The combination of venetoclax and bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation. Further studies are warranted to determine the mechanisms for the synergism between venetoclax and bendamustine in high-risk T-ALL.
Topics: Humans; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Drug Synergism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Jurkat Cells; Apoptosis; Cell Proliferation
PubMed: 38936885
DOI: 10.21873/invivo.13624 -
International Journal of Molecular... Jun 2024The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential...
The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential therapeutic targets. Typical genomic analyses have directed attention toward the most commonly mutated genes. However, assessing the contribution of mutations to cancer phenotypes is crucial. Therefore, we estimated the cancer effects (scaled selection coefficients) for somatic substitutions in T-cell and B-cell cohorts, revealing key insights into mutation contributions. Cancer effects for well-known, frequently mutated genes like and in B-ALL were high, which underscores their importance as therapeutic targets. However, less frequently mutated genes , , and also demonstrated high cancer effects, suggesting pivotal roles in the development of leukemia when present. In T-ALL, and are less frequently mutated than in B-ALL. However, their cancer effects when present are high in both subtypes. Mutations in and were not at high prevalence, yet exhibited some of the highest cancer effects in individual T-cell ALL patients. Even , with a low prevalence and relatively modest cancer effect, is potentially highly relevant for the epistatic effects that its mutated form exerts on other mutations. Prioritizing investigation into these moderately frequent but potentially high-impact targets not only presents novel personalized therapeutic opportunities but also enhances the understanding of disease mechanisms and advances precision therapeutics for pediatric ALL.
Topics: Humans; Child; Mutation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; B-Lymphocytes
PubMed: 38928295
DOI: 10.3390/ijms25126589 -
International Journal of Molecular... Jun 2024While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute...
While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute lymphoblastic leukemia (ALL), metabolic studies are still lagging, especially regarding how the metabolism differs between healthy and diseased individuals. T-cell ALL (T-ALL) is an aggressive hematological neoplasm deriving from the malignant transformation of T-cell progenitors characterized by frequent NOTCH1 pathway activation. The aim of our study was to characterize tumor and plasma metabolomes during T-ALL development using a NOTCH1-induced murine T-ALL model (ΔE-NOTCH1). In tissue, we found a significant metabolic shift with leukemia development, as metabolites linked to glycolysis (lactic acid) and Tricarboxylic acid cycle replenishment (succinic and malic acids) were elevated in NOTCH1 tumors, while metabolites associated with lipid oxidation (e.g., carnitine) as well as purine and pyrimidine metabolism were elevated in normal thymic tissue. Glycine, serine, and threonine metabolism, glutathione metabolism, as well as valine, leucine, and isoleucine biosynthesis were enriched pathways in tumor tissue. Phenylalanine and tyrosine metabolism was highly enriched in plasma from leukemia-bearing mice compared to healthy mice. Further, we identified a metabolic signature consisting of glycine, alanine, proline, 3-hydroxybutyrate, and glutamic acid as potential biomarkers for leukemia progression in plasma. Hopefully, the metabolic differences detected in our leukemia model will apply to humans and contribute to the development of metabolism-oriented therapeutic approaches.
Topics: Animals; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Mice; Receptor, Notch1; Metabolomics; Biomarkers, Tumor; Metabolome; Disease Models, Animal
PubMed: 38928249
DOI: 10.3390/ijms25126543 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the characteristics and prognosis of patients with mucormycosis after chemotherapy for acute leukemia, and to strengthen understanding of the disease.
OBJECTIVE
To analyze the characteristics and prognosis of patients with mucormycosis after chemotherapy for acute leukemia, and to strengthen understanding of the disease.
METHODS
7 cases of acute leukemia (AL) patients diagnosed with mucormycosis by metagenomic next generation sequencing (mNGS) after chemotherapy at the First Affiliated Hospital of Bengbu Medical College from October 2021 to June 2022 were collected, and their clinical data, including clinical characteristics, diagnosis, treatment, and prognosis, were retrospectively analyzed.
RESULTS
Among the 7 patients with AL complicated with mucormycosis, there were 3 males and 4 females, with a median age of 52(20-59) years. There were 6 cases of acute myeloid leukemia (AML) and 1 case of acute lymphocytic leukemia (ALL). Extrapulmonary involvement in 4 cases, including 1 case suspected of central nervous system involvement. The median time for the occurrence of mucor infection was 16(6-69) days after chemotherapy and 19(14-154) days after agranulocytosis. The main clinical manifestations of mucormycosis were fever (7/7), cough (3/7), chest pain (3/7) and dyspnea (1/7). The most common chest CT imaging findings were nodules, patchy or mass consolidation (6/7). All patients were treated with posaconazole or voriconazole prophylaxis during neutropenia phase. 5 patients died within 8 months, and the median time from diagnosis to death was 1 month.
CONCLUSION
Although prophylactic antifungal therapy is adopted, patients with acute leukemia still have a risk of mucor infection during the neutropenia phase. Fever is the main manifestation in the early stage of mucor infection. The use of intravenous antifungal drugs alone is ineffective and there is a high mortality rate in acute leukemia patients with mucormycosis.
Topics: Humans; Mucormycosis; Male; Female; Adult; Middle Aged; Prognosis; Retrospective Studies; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antifungal Agents; Young Adult; Leukemia
PubMed: 38926954
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.006 -
Journal of Experimental & Clinical... Jun 2024Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell...
BACKGROUND
Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) patients, and how it affects tumorigenesis and drug response. Our research focuses on investigating the role of enhancers in sustaining oncogenic transformation in children with BCP-ALL.
METHODS
We used ATAC-seq to study the accessibility of chromatin in pediatric BCP-ALL at three different stages-onset, remission, and relapse. Using a combination of computational and experimental methods, we were able to analyze the accessibility landscape and focus on the most significant cis-regulatory sites. These sites were then functionally validated through the use of Promoter capture Hi-C in a primary cell line model called LAL-B, followed by RNA-seq and genomic deletion of target sites using CRISPR-Cas9 editing.
RESULTS
We found that enhancer activity changes during cancer progression and is mediated by the production of enhancer RNAs (eRNAs). CRISPR-Cas9-mediated validation of previously unknown eRNA productive enhancers demonstrated their capability to control the oncogenic activities of the MYB and DCTD genes.
CONCLUSIONS
Our findings directly support the notion that productive enhancer engagement is a crucial determinant of the BCP-ALL and highlight the potential of enhancers as therapeutic targets in pediatric BCP-ALL.
Topics: Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Enhancer Elements, Genetic; Cell Transformation, Neoplastic; Disease Progression; Child
PubMed: 38926853
DOI: 10.1186/s13046-024-03075-y -
Clinica Chimica Acta; International... Jun 2024Pregnancy induces physiological changes that can affect serologic and immunologic markers, potentially resulting in lower or undetectable haptoglobin values compared to...
BACKGROUND-AIM
Pregnancy induces physiological changes that can affect serologic and immunologic markers, potentially resulting in lower or undetectable haptoglobin values compared to non-pregnant counterparts. Such variations may lead to inaccurate diagnosis of hemolysis.
METHODS
We report a case of a patient in second trimester of pregnancy receiving induction chemotherapy due to B-cell acute lymphocytic leukemia with undetectable haptoglobin levels in a routine laboratory sample collected less than 12 h posttransfusion of red cell unit. Despite undetectable haptoglobin, lactate dehydrogenase (LD) was within reference intervals (RI). The patient was evaluated for acute hemolytic transfusion reaction (AHTR) and followed up. Haptoglobin levels showed an upward trend during follow-up visits, reaching 15 mg/dL, and within RI in the third trimester.
RESULTS
The patient did not meet the Center for Disease Control (CDC) criteria for AHTR. Alternative explanations for the observed laboratory findings were explored. Undetectable haptoglobin levels were attributed to various factors, including recent RBC transfusion, pregnancy-related physiological changes, and potential hyperhydration treatment plan due to chemotherapy.
CONCLUSION
This case underscores the importance of cautious interpretation of laboratory results in pregnant patients, necessitating trimester-specific reference intervals for haptoglobin. A multidisciplinary approach to patient care is crucial for accurate diagnosis and management.
PubMed: 38917868
DOI: 10.1016/j.cca.2024.119829 -
Current Treatment Options in Oncology Jun 2024For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of... (Review)
Review
For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.
PubMed: 38916714
DOI: 10.1007/s11864-024-01213-4 -
Journal of Cancer Research and Clinical... Jun 2024Leukemia-associated fusion genes are closely related to the occurrence, development, diagnosis, and treatment of leukemia. DNA microarrays and second-generation...
PURPOSE
Leukemia-associated fusion genes are closely related to the occurrence, development, diagnosis, and treatment of leukemia. DNA microarrays and second-generation sequencing have discovered multiple B-ALL fusion genes. We identified a novel MEF2C::SS18L1 fusion gene in a child diagnosed with B-ALL. This study investigates the oncogenicity and prognosis of this fusion gene in B-ALL.
METHODS
A child with B-ALL who has a MEF2C::SS18L1 fusion is reported as a newly discovered case. Compared the breakpoints, structural domains, clinical phenotypes, and differential expression genes of MEF2C::SS18L1 and MEF2D::SS18.Using "ONCOFUSE" software, the carcinogenicity of MEF2C::SS18L1 is predicted. Using whole transcriptome sequencing, we analyze the breakpoints and the secondary structure of the fusion protein. Further, we compared the structures, differentially expressed genes, and clinical phenotypes of MEF2D and MEF2C fusion genes by DESeq, GO functional enrichment, and flow cytometry immunophenotyping analysis.
RESULTS
Whole transcriptome sequencing identified a MEF2C::SS18L1 fusion transcript in a 3-year-old child with B-ALL. The MADS box, MEF structural domain, HJURP_C structural domain, and TAD I structural domain of MEF2C, and the QPGY structural domain of SS18L1, make up the fusion protein. "Oncofuse" found a 0.99 Bayesian probability that the fusion gene drives cancer. The breakpoint positions, fusion protein secondary structures, differentially expressed genes, and clinical characteristics of this patient were identical to those with MEF2D::SS18 fusion gene.
CONCLUSION
We identified a novel MEF2C::SS18L1 fusion gene in childhood ALL, which shares similar structural and clinical characteristics with MEF2D::SS18. Further studies with more samples should be conducted in future.
Topics: Humans; MEF2 Transcription Factors; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Male; Child, Preschool; Child; Female
PubMed: 38907739
DOI: 10.1007/s00432-024-05846-8