Intracellular Lysozyme in Mature Neutrophils and Blast Cells in Acute Leukemia

Abstract Intracellular lysozyme (muramidase) activity was measured in leukemic blasts and mature neutrophilic granulocytes from 20 patients with acute myeloblastic and myelomonocytic leukemia and in 11 patients with acute lymphoblastic leukemia after differential centrifugation of cells in Ficoll and extraction of lysozyme with n-butanol. Considerable abnormalities in cellular lysozyme activity were found both in qualitative and quantitative terms. In contrast to normal myeloblasts, leukemic blasts of the myeloid series contained lysozyme in a considerable number of cases. Although no clear-cut distinction was seen, those patients with positive blast lysozyme reactivity tended to have the highest plasma lysozyme levels, whereas no good correlation was found between morphologic differentiation along myeloblastic or monocytoblastic lines of blasts and lysozyme reactivity. Calculations of the magnitude of lysozyme production in acute leukemias with high plasma lysozyme concentration was compatible with the hypothesis that in these cases lysozyme must be secreted by intact blasts and that, consequently, plasma lysozyme activity reflects the total leukemic cell mass. In mature neutrophilic granulocytes from patients with acute myeloblastic and myelomonocytic leukemia in relapse, the mean lysozyme activity was significantly decreased, although a great deal of variation was found. In remission, neutrophil lysozyme activity seemed to increase; among several possibilities this might be a reflection of different clones being operative in relapse and remission. In acute lymphoblastic leukemia, lysozyme activity in neutrophils was constantly low in relapse and increased to normal following induction of remission, which may be the main explanation of the low plasma lysozyme activity found in this type of acute leukemia. It is unexplained and puzzling why intraneutrophil lysozyme activity is low in a leukemic type where the myeloid cells are not believed to be primarily leukemic; one possible reason might be an effect of cell-to-cell interaction with the leukemic cell population.

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Acute Leukemia

10.2310/im.1247 ◽

2016 ◽

Author(s):

Richard A. Larson ◽

Roland B Walter

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Who Classification ◽

Lymphoblastic Leukemia ◽

World Health ◽

Acute Leukemias ◽

Acute Myeloid

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classiﬁcation of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 1 highly rendered figure, 9 tables, and 117 references.

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Clonal Evolution of B-Cell Acute Lymphoblastic Leukemia with del(9)(p13p21) into Mixed Phenotype Acute Leukemia Presenting as an Isolated Testicular Relapse

Reports ◽

10.3390/reports2030018 ◽

2019 ◽

Vol 2 (3) ◽

pp. 18 ◽

Cited By ~ 1

Author(s):

Miller ◽

Park ◽

Saxe ◽

Lew ◽

Raikar

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Acute Leukemias ◽

Cytogenetic Aberrations ◽

Mixed Phenotype Acute Leukemia ◽

Cell Acute Lymphoblastic Leukemia ◽

Mixed Phenotype

Lineage switch in acute leukemias is a well-reported occurrence; however, most of these cases involve a switch from either lymphoid to myeloid or myeloid to lymphoid lineage. Here, we report a case of a 14-year-old male with B-cell acute lymphoblastic leukemia (B-ALL) who initially responded well to standard chemotherapy but then later developed mixed phenotype acute leukemia (MPAL) at relapse, likely reflecting a clonal evolution of the original leukemia with a partial phenotypic shift. The patient had a del(9)(p13p21) in his leukemia blasts at diagnosis, and the deletion persisted at relapse along with multiple additional cytogenetic aberrations. Interestingly, the patient presented with an isolated testicular lesion at relapse, which on further analysis revealed both a lymphoid and myeloid component. Unfortunately, the patient did not respond well to treatment at relapse and eventually succumbed to his disease. To our knowledge, an isolated extramedullary MPAL at relapse in a patient with previously diagnosed B-ALL has not been reported in the literature before.

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Biology of t(6;11) Fusion Proteins and Their Role in MLL-Rearranged Acute Leukemia Lineage Determination

Blood ◽

10.1182/blood-2019-123070 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5033-5033

Author(s):

Arpita Kundu ◽

Eric Kowarz ◽

Jennifer Reis ◽

Rolf Marschalek

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Acute Leukemia ◽

Fusion Proteins ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocation ◽

Fusion Genes ◽

Disease Phenotype ◽

Acute Leukemias

Chromosomal translocations are genetic rearrangements where a chromosomal segment is transferred to a non-homologous chromosome which give rise to novel chimeras. Chromosomal rearrangements play a significant role in the development of acute leukemias (acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML)). Chromosomal translocation events occurring at 11q23 involving the KMT2A or Mixed-Lineage Leukemia (MLL) gene (n=102) can be diagnosed in about 5-10% of all acute leukemia patients (Marschalek Ann Lab Med 2016), especially prevalent in infant acute leukemias (up to 70% of cases). Different chromosomal translocation partner genes (such as AF4, AF6, AF9orENL and ELL) account for the majority of leukemia cases and have their genomic breakpoints within a major breakpoint cluster region (BCR intron 9-11; Meyer et. al. Leukemia 2018). Some rearrangements are specifically associated with particular disease phenotype e.g. the majority of ALL patients (~ 90%) are mainly caused by the following gene fusions, MLL-AF4, MLL-AF9, MLL-ENL. We are interested in a rare but yet drastic chromosomal translocation t(6;11)(q27;q23) which fuses KMT2A/MLL to Afadin (AFDN/AF6) gene. This chromosomal rearrangement has a very poor prognosis (survival-rate is ~10%) and is predominantly diagnosed in patients with high-risk AML. In this project, we investigate the molecular consequences of two different MLL-AF6 fusions and their corresponding reciprocal AF6-MLL fusions. MLL-AF6 fusions are mainly occurring within MLL intron 9 to 11 and are associated with an AML disease phenotype, while the same fusion occurring within the minor breakpoints region in MLL intron 21 until exon (ex) 24 are mainly diagnosed with T-ALL (T-cell acute lymphoblastic leukemia) disease phenotype. The molecular mechanism that determines the resulting disease phenotype is yet unknown. Therefore, we cloned all of these t(6;11) fusion proteins in order to investigate the functional consequences of the two different breakpoints (MLLex1-9::AF6ex2-30, AF6ex1::MLLex10-37; MLLex1-21::AF6ex2-30, AF6ex1::MLLex22-37). All 4 fusion genes were introduced into our inducible Sleeping Beauty system (Ivics et. al. Mobile DNA 2010; Kowarz et. al. Biotechnol J. 2015) and stably transfected reporter cell lines. Basically, these 4 fusion proteins differ only in the presence or absence of their Plant homeodomain 1-3/Bromodomain (PHD1-3/BD) domain (see Figure 1). The PHD domain regulates the epigenetic and transcriptional regulatory functions of wildtype MLL. Subsequently, we analyzed gene expression differences by the MACE-Seq (Massive Analyses of cDNA Ends). MACE data revealed fundamental differences in gene expression profiles when analyzing the two different sets of t(6;11) fusion genes. The resulting profiles have similarities to either AML or T-ALL and might give a rational explanation for the different lineages in these t(6;11) patients. Altogether, these results notably indicate that our study will provide a novel insight into this type of high-risk leukemia and subsequently will be useful for developing of novel and appropriate therapeutic strategies against acute leukemia. Disclosures No relevant conflicts of interest to declare.

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14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T and myeloid immature acute leukemia

Blood ◽

10.1182/blood.2020010510 ◽

2021 ◽

Author(s):

Danika Di Giacomo ◽

Roberta La Starza ◽

Paolo Gorello ◽

Fabrizia Pellanera ◽

Zeynep Kalender Atak ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Acute Leukemia ◽

Mammalian Cells ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Fusion Transcript ◽

Specific Expression ◽

Acute Leukemias ◽

Distinct Subgroup

Acute leukemias (AL) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by co-expression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML M0 or M1), T/myeloid mixed phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell Acute Lymphoblastic Leukemia (T-ALL) (58 ETP, 178 non-ETP, 8 T/M MPAL, 89 not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3,6% of T-ALL) harbouring four types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n=7), t(6;14)(q25.3;q32) (n=9), t(7;14)(q21.2;q32) (n=2) and t(8;14)(q24.2;q32) (n=2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, while the other three rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker, which was present at diagnosis but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently DNMT3A, TET2 and/or WT1 gene. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B positive AL from AML, T-ALL, and ETP-ALL. Remarkably, ex-vivo drug sensitivity profile identified a panel of compounds with effective antileukemic activity.

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Acute Leukemia

10.2310/fm.1247 ◽

2021 ◽

Author(s):

Richard A. Larson ◽

Roland B Walter

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Who Classification ◽

Lymphoblastic Leukemia ◽

World Health ◽

Acute Leukemias ◽

Acute Myeloid

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classiﬁcation of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 2 figures, 15 tables, and 119 references. Keywords: Acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, cancer, cytogenetics, chromosomal abnormality

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MicroRNA Expression Signatures Accurately Discriminate Acute Lymphoblastic Leukemia from Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.231.231 ◽

2007 ◽

Vol 110 (11) ◽

pp. 231-231

Author(s):

Shuangli Mi ◽

Jun Lu ◽

Miao Sun ◽

Zejuan Li ◽

Hao Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Target Genes ◽

Lymphoblastic Leukemia ◽

Acute Leukemias ◽

In Vivo Models ◽

Acute Myeloid

Abstract Human acute leukemias include acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It is estimated that 5,200 and 13,410 cases will be diagnosed with and 1,420 and 8,990 will die of ALL and AML, respectively, in the United States in 2007. Although remarkable progress has been made in the past decades in the treatment and in the understanding of the biology of acute leukemias, the 5-year overall survival rate of patients with AML is only approximately 22%, which is much lower than that of ALL patients (65%; http://seer.cancer.gov). One of the most exciting recent findings is the discovery of an abundant class of small (∼22 nt), non-(protein-)coding RNAs, called microRNAs (miRNAs, miRs), which can function as oncogenes and tumor suppressors, whose deregulation is clearly associated with the development of cancer. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify novel markers for diagnosis and treatment of acute leukemia, we have performed a large-scale miRNA expression profiling assay with a bead-based flow cytometric method and identified 27 differentially expressed miRNAs. Among them, miR-128a and b are significantly overexpressed while let-7b and miR-223 are significantly down-regulated in ALL compared to AML. They are the most discriminatory miRNAs between ALL and AML. Using the expression signatures of any two of the four most significantly discriminatory miRNAs in diagnosis of ALL and AML resulted in an accuracy rate of 97–100%. The differential expression patterns of these four miRNAs were validated further through quantitative real-time PCR on 98 acute leukemia samples covering most of the common cytogenetic subtypes of AML and B- and T-cell ALL, along with 10 normal controls. Furthermore, we found that overexpression of miR-128a and b in ALL was at least partly associated with hypomethylation, rather than amplification of DNA locus copy. Moreover, several important target genes of these four miRNAs have also been validated. We are currently exploring the role of these four miRNAs and their critical target genes in leukemogenesis and in the determination of lineage fate during leukemia development using in vitro and in vivo models. This work will enhance our understanding of the biological role of these miRNAs and their targets in leukemogenesis, and in determining the lineage fate of acute leukemia.

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Acute Leukemia

10.2310/tywc.1247 ◽

2018 ◽

Author(s):

Richard A. Larson ◽

Roland B Walter

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Who Classification ◽

Lymphoblastic Leukemia ◽

World Health ◽

Acute Leukemias ◽

Acute Myeloid

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Pattern of childhood acute leukemia presentation at a tertiary hospital in Nigeria: a five-year review

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20184202 ◽

2018 ◽

Vol 5 (6) ◽

pp. 2123

Author(s):

Adewumi B. Oyesakin ◽

Vincent E. Nwatah ◽

Nwankwo U. Ukpai ◽

Ekaette I. David ◽

Tamunomieibi T. Wakama ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Clinical Features ◽

Childhood Leukemia ◽

Lymphoblastic Leukemia ◽

Tertiary Hospital ◽

Cross Sectional ◽

Acute Leukemias ◽

Lost To Follow Up

Background: Acute leukemia is the most common childhood malignancy but its occurrence in low- and middle-income countries are under-reported. Its pattern of presentation varies depending on several factors. The objective of this report is to determine the pattern of presentation of acute leukemias in children at a tertiary hospital in Nigeria.Methods: A retrospective cross-sectional study of children managed for acute leukemia at the Paediatric Department in a 5-year period. Of 31 patients, 27 had adequate records, which were reviewed. Data collected include patient’s demographics, clinical features and treatment outcome.Results: There were 16 males and 11 females, aged 8 months to 16 years (mean 7.45 years ±4.75 SD). The pattern of clinical features were fever (85.2%), pallor (92.6%) and splenomegaly (51.9%). The specific leukemia type ratio for Acute Myeloid leukemia (AML) and Acute lymphoblastic leukemia (ALL) was 1: 2.9. The parents of three patients took their children away before commencement of treatment, one patient completed treatment and 6 (22.2%) died before completing treatment. Nearly half of the patients were lost to follow up to seek alternative care while 9 (33.3%) of the patients were in remission at last follow up. Lost to follow-up was found not to be significantly associated with socioeconomic status, age and sex respectively.Conclusions: Acute lymphoblastic leukemia remains the predominant type of childhood leukemia in our setting. Majority of the patients presented with fever and pallor moreover the default to follow-up plagues treatment completion.

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Poor Prognosis Biomolecular Factors Are Highly Frequent in Childhood Acute Leukemias From Oaxaca, Mexico

Technology in Cancer Research & Treatment ◽

10.1177/1533033820928436 ◽

2020 ◽

Vol 19 ◽

pp. 153303382092843

Author(s):

Gerardo Juárez-Avendaño ◽

Nuria Citlalli Luna-Silva ◽

Euler Chargoy-Vivaldo ◽

Laura Alicia Juárez-Martínez ◽

Mayra Noemí Martínez-Rangel ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

B Cell ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Acute Leukemias ◽

Cell Acute Lymphoblastic Leukemia ◽

Acute Myeloid

Objective: To investigate the cellular and molecular epidemiology of acute leukemias in vulnerable populations of children and adolescents in Oaxaca de Juarez, Mexico. Material and Methods: Descriptive, cross-sectional and retrospective study, conducted from 2014 to 2018 in which profiles of molecular and immunophenotypic aberrations were investigated in children and adolescents diagnosed with acute leukemia, by evaluating 28 molecular abnormalities by HemaVision-Q28 multiplex RT-PCR kit and standardized EuroFlow Immunophenotyping of bone marrow cells. Results: We included 218 patients, with 82.5% younger than 14 years and 17.5% adolescents. The median age was 9 years and a main peak of incidence was recorded at age of 4 to 5 years. B-cell acute lymphoblastic leukemia was diagnosed in 70.64% of all cases, acute myeloid leukemia was in 22.48%, T-cell acute lymphoblastic leukemia in 6.42%, and mixed lineage acute leukemia in 0.46% of cases. Overall, chromosomal translocations were positive in 29.82% of cases. While 65.31% of patients with acute myeloid leukemia reported aberrancies, only in 18.83% of B-cell acute lymphoblastic leukemia cases genetic abnormalities were obvious. Surprisingly, most prevalent translocations in B-cell acute lymphoblastic leukemia were t(9;22) in 20.7%, followed by t(4;11) in 17.2% and t(6;11) in 13.8%, whereas patients with acute myeloid leukemia showed t(15;17) in 40.6% and t(8;21) in 21.9%. In contrast, an homogeneous expression of t(3;21) and t(6;11) was recorded for T-cell acute lymphoblastic leukemia and mixed lineage acute leukemia cases, respectively. Except for t(1;19), expressed only by pre-B cells, there was no association of any of the studied translocations with differentiation stages of the B-leukemic developmental pathway. Conclusion: Our findings identify near 50% of patients with acute lymphoblastic leukemia at debut with high-risk translocations and poor prognosis in B-cell acute lymphoblastic leukemia as well as an unexpected increase of acute myeloid leukemia cases in young children, suggesting a molecular shift that support a higher incidence of poor prognosis cases in Oaxaca.

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Factors Associated with Pediatric Acute Leukemia. Medellín, Colombia. 2008-2011

International Journal of Cancer Research & Therapy ◽

10.33140/ijcrt/03/01/00005 ◽

2018 ◽

Vol 3 (1) ◽

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Metropolitan Area ◽

Lymphoblastic Leukemia ◽

Health Planning ◽

Daily Consumption ◽

Lymphoid Leukemia ◽

Acute Leukemias ◽

Factors Associated ◽

Acute Lymphoid Leukemia

Introduction: Acute leukemias have generated great interest in the world to be within the ten most common cancers, and children ranks first in malignancies. Objective: Analyze the demographic, genetic, environmental, pre and perinatal factors associated with acute lymphoblastic leukemia in pediatric acute leukemia group in Medellin during 2008 - 2011. Methods: Cross-sectional study in children under 15 years with leukemia acute in Medellin and the metropolitan area during 2008 -2011.Se implemented a logistic regression model to identify factors associated with acute lymphoblastic leukemia. Results: 80 patients were studied. Factors associated with multivariate analysis were acute lymphoid leukemia: Daily consumption of alcohol by the father (OR: 3.95; 95% CI 1.26 to 7.55) and that the child had been breastfed (OR: 0.036, 95% CI 0.002 to 0.83). Conclusions: The identification of risk and protective factors associated with acute lymphoid leukemia (ALL) in Medellin and its metropolitan area; they are a useful tool for health planning input.

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