scholarly journals Novel Markers in Pediatric Acute Lymphoid Leukemia: The Role of ADAM6 in B Cell Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Laila Alsuwaidi ◽  
Mahmood Hachim ◽  
Abiola Senok
Keyword(s):  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Expression Patterns ◽  
Molecular Profile ◽  
Lymphoid Leukemia ◽  
Childhood All ◽  
B Cell Leukemia ◽  
Chromosomal Changes ◽  
Homozygous Deletions

BackgroundThe extensive genetic heterogeneity found in the B cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype of childhood ALL represents a potential repository of biomarkers. To explore this potential, we have carried out in silico analysis of publicly available ALL datasets to identify genetic biomarkers for childhood BCP-ALL, which could be used either individually or in combination as markers for early detection, risk stratification, and prognosis.MethodsTo explore novel genes that show promising clinical and molecular signatures, we examined the cBioPortal online tool for publicly available datasets on lymphoid cancers. Three studies on lymphoblastic and lymphoid leukemia with 1706 patients and 2144 samples of which were identified. Only B-Lymphoblastic Leukemia/Lymphoma samples (n = 1978) were selected for further analysis. Chromosomal changes were assessed to determine novel genomic loci to analyze clinical and molecular profiles for the leukemia of lymphoid origin using cBioPortal tool.ResultsADAM6 gene homozygous deletions (HOM:DEL) were present in 59.60% of the profiled patients and were associated with poor ten years of overall patients’ survival. Moreover, patients with ADAM6 HOM:DEL showed a distinguished clinical and molecular profile with higher Central Nervous System (CNS) sites of relapse. In addition, ADAM6 HOM:DEL was significantly associated with unique microRNAs gene expression patterns.ConclusionADAM6 has the potential to be a novel biomarker for the development and progress of BCP- ALL.

scholarly journals Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia

2021 ◽  
Author(s):  
Briana Fitch ◽  
Mi Zhou ◽  
Jamilla Situ ◽  
Sangeetha Surianarayanan ◽  
Melissa Q Reeves ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Inflammatory Responses ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Lymphoid Leukemia ◽  
Childhood Infections ◽  
Microbial Dysbiosis ◽  
B Cell Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that IL-10 deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, MIP-1β/CCL4, and G-CSF). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create risk of leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.

The BCL-2 Antagonist ABT-737 Is Highly Effective on Primary Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 155-155
Author(s):  
Maria Rosaria Ricciardi ◽  
Chiara Gregorj ◽  
Fabiana De Cave ◽  
Paola Bergamo ◽  
Samantha Decandia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Annexin V ◽  
Lymphoid Leukemia ◽  
Childhood All ◽  
Leukemia Cell Lines

Abstract The treatment of adult acute lymphoblastic leukemia (ALL) remains unsatisfactory. A potential hope is now given to Philadelphia-positive cases by targeted treatment modalities. Among other pathways involved in cell proliferation, we have recently demonstrated (Blood2007; 109:5473) the unfavorable role of ERK1/2 phosphorylation as an independent predictor of complete remission (CR) in adult ALL, suggesting the potential therapeutic value of other targeted therapies. The B-cell leukemia/lymphoma 2 (Bcl-2) family of proteins are important regulators of apoptosis and are frequently found aberrantly expressed, particularly in lymphoid malignancies. The role of Bcl-2 overexpression in tumorigenesis and chemoresistance prompted us to investigate whether the inhibition of the antiapoptotic function may result also in ALL in an attractive therapeutic strategy. In this study, we thus investigated the cell cycle and apoptotic effects of ABT-737 (kindly provided by Abbott Laboratories), a Bcl-2 (BH3) inhibitor, on both lymphoid leukemia cell lines and primary adult and childhood ALL cells. The lymphoid leukemia cell lines CEM and MOLT-4 were exposed to increasing concentrations of ABT-737 (from 0.1 to 1 μM) up to 72 hours. A dose- and time-dependent cell growth arrest and induction of apoptosis was found. In fact, measuring the subG0/1 peak at 48 hours, the levels of apoptosis increased in the CEM cell line from 14.1% (DMSO) to 34.4%, 64.5%, 86.5% and 98.6% at ABT-737 concentrations of 0.1, 0.25, 0.5 and 1 μM, respectively. Similarly, 48 hours of exposure to ABT-737 increased in MOLT-4 the Annexin V-positive cells from 7.2% to 64.2%. The effects of ABT-737 were then examined on primary blasts from 9 ALL patients (6 adults and 3 children). Bone marrow aspirates with a blast infiltration >70% were obtained at diagnosis from patients broadly characterized for clinical and biological parameters, as well as therapeutic response. ALL cells were cultured in vitro with ABT-737 (at increasing concentrations from 0.01 to 1 μM) for 24 hours. A significant decrease in viability was observed at 0.01 μM (p=0.008) with a remarkable dose-dependent increase of apoptosis. In fact, Annexin V-positive cells increased from a mean baseline value of 16.8% ± 8.8 to 43.6% ± 22.8 (p=0.04), 66% ± 21.3 (p=0.0001), 70.3% ± 26.9 (p=0.04), 74.6% ± 18.9 (p=0.03) and 76.2% ± 11.8 (p<0.0001) in the presence of ABT-737 at 0.01, 0.1, 0.25, 0.5 and 1 μM, respectively. A significant cell killing was demonstrated in all samples (9/9), including Ph-positive ALL. No significant cell cycle changes were instead detected even at higher concentration of ABT-737. In summary, our study shows for the first time a potent growth-inhibitory and pro-apoptotic activity of the Bcl-2 antagonist ABT-737, at nanomolar concentrations, on primary cells from adult and childhood ALL samples. These results prompt to further extend pre-clinical studies in the different biologically-defined subset of ALL and suggest a potential clinical development of a Bcl-2 family inhibitor in this disease.

Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1765-1767 ◽  
Author(s):  
Rashmi B. Prasad ◽  
Fay J. Hosking ◽  
Jayaram Vijayakrishnan ◽  
Elli Papaemmanuil ◽  
Rolf Koehler ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
The United Kingdom ◽  
Genome Wide ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Association Data ◽  
The Relationship

Abstract Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 ×10−22), 1.80 (P = 5.90 × 10−28), and 1.27 (P = 4.90 × 10−6), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (ORper-allele = 1.53, 95% confidence interval, 1.44-1.62; Ptrend = 3.49 × 10−42), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases.

scholarly journals BCL6 Enables RAS-Mediated Pre-B Cell Transformation in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3570-3570
Author(s):  
Christian Hurtz ◽  
Huimin Geng ◽  
Gang Xiao ◽  
Mignon L. Loh ◽  
B. Hilda Ye ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Erk Pathway ◽  
Childhood All ◽  
Expression Levels ◽  
Bcl6 Expression

Abstract Background & Hypothesis: The transcriptional repressor and proto-oncogene BCL6 has recently been identified as a therapeutic target in subtypes of diffuse large B cell lymphoma (DLBCL) and as mediator of a novel for of drug-resistance in Ph+ acute lymphoblastic leukemia (ALL; Duy et al., Nature 2011). A previous senescence rescue screen identified BCL6 as a key factor that bypassed senescence and thereby enabled RAS-mediated transformation of mouse embryonic fibroblasts (Shvarts et al., Genes Dev 2002). Since ~50% of pediatric cases of ALL carry genetic lesions that result in hyperactivation of the Ras-Erk pathway (Zhang et al., Blood 2012), we tested the role of Bcl6 in this large subgroup of childhood leukemia. Results: Mutations leading to hyperactivation of the Ras-Erk pathway are found in about 50% of childhood ALL cases (Zhang et al., 2012). Among 26 ALL xenografts, we found 9 cases with constitutive Erk-T202/Y204 phosphorylation, which was paralleled by elevated expression levels of BCL6 in these cases. Studying mouse pre-B cells that were engineered with a doxycycline-inducible NRASG12D mutant, we were able to directly measure the consequences of acute activation of the Ras-Erk pathway on BCL6 expression levels. First we incubated the cells with doxycycline to induce the expression of NRASG12D and then harvested the cells at different times point to test for BCL6 protein and mRNA expression levels. Interestingly, after 24h NRASG12D-TetO pre-B cells cells showed strong upregulation of BCL6 at the mRNA (352-fold) and protein level (15-fold). Upregulation of BCL6 in response to NRASG12D-activation was sensitive to treatment with the MEK kinase inhibitor PD325901, upstream of Erk, suggesting that BCL6 expression is a consequence of Erk activation in pre-B cells. Likewise, treatment of patient-derived pre-B ALL cells with the MEK inhibitor PD325901 reversed BCL6 expression, as demonstrated by quantitative RT-PCR and Western blot. From one patient, a diagnostic (KRAS wildtype) and a relapse sample with an acquired KRASG12V mutation were available. Consistent with specific expression of BCL6 in the KRASG12V relapse ALL sample, only KRASG12V ALL cells from the relapse but not wildtype cells from the diagnostic sample were sensitive to a retro inversoBCL6 peptide inhibitor (RI-BPI; Cerchietti et al., 2009). Development of a genetic mouse model for inducible ablation of Bcl6. These findings suggest an important role of BCL6 as a cofactor of RAS-driven pre-B cell transformation, comparable to previous findings in mouse embryonic fibroblasts. To directly test a mechanistic role of Bcl6 in RAS-mediated pre-B cell transformation, we generated a novel mouse model for inducible Cre-mediated deletion of Bcl6 exons 5-10, flanked by loxP sites. For lineage-specific deletion in vivo, we crossed these mice with an Mb1-Cre deleter strain, in which Bcl6 was deleted in pro-B cells, resulting in a differentiation block at the pre-B cell stage. Interestingly, Mb1-Cre x Bcl6fl/fl B cell lineage cells could be transduced with NRASG12D retroviral vectors, however these cells did not give rise to leukemia when injected into congenic recipients, whereas NRASG12D-transduced Bcl6fl/fl pro-B cells that retained Bcl6 function developed B cell lineage leukemia in all transplant recipients. In a second experiment, we transformed Bcl6fl/fl pro-B cells with NRASG12D and induced Cre with a second, tamoxifen-inducible vector in full-blown leukemia cells. Acute ablation of Bcl6 in NRASG12D ALL cells completely abrogated the ability of NRASG12DALL cells to form colonies in methylcellulose and resulted in rapid apoptosis and depletion from the cell culture. We conclude that BCL6 is not only required for the initiation of RAS-driven ALL in vivo but also for the maintenance of fully established RAS-driven leukemia. Conclusion: These findings provide genetic evidence for BCL6 function as a critical cofactor of RAS-mediated transformation in childhood ALL. Inhibition of BCL6 in RAS-driven ALL may be useful to prevent leukemia relapse after initial remission (Bcl6-dependent leukemia-initiation) and also to achieve profound remission by combining conventional cytotoxic therapies with BCL6 inhibition (e.g. RI-BPI). Disclosures No relevant conflicts of interest to declare.

scholarly journals Towards prevention of childhood ALL by early-life immune training

Blood ◽  
2021 ◽  
Author(s):  
Julia Hauer ◽  
Ute Fischer ◽  
Arndt Borkhardt
Keyword(s):  
B Cell ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Host Responses ◽  
Childhood All ◽  
Cell Clones ◽  
Runx1 Gene ◽  
Immune Challenges ◽  
Fetal Hematopoiesis ◽  
Overt Leukemia

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common form of childhood cancer. Chemotherapy is associated with life-long health sequelae and fails in approximately 20% of cases. Thus, prevention of leukemia would be preferable to treatment. Childhood leukemia frequently starts before birth, during fetal hematopoiesis. A first genetic hit (e.g. the ETV6-RUNX1 gene fusion) leads to the expansion of pre-leukemic B-cell clones, which are detectable in healthy newborn cord blood (up to 5%). These pre-leukemic clones give rise to clinically overt leukemia in only about 0.2% of carriers. Experimental evidence suggests that a major driver of conversion from the pre-leukemic to the leukemic state is exposure to immune challenges. Novel insights have shed light on immune host responses and how they shape the complex interplay between (A) inherited or acquired genetic predispositions, (B) exposure to infection, and (C) abnormal cytokine release from immunologically untrained cells. Here, we integrate the recently emerging concept of "trained immunity" into existing models of childhood BCP-ALL and suggest future avenues towards leukemia prevention.

scholarly journals Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
T. M. Cardesa-Salzmann ◽  
A. Simon ◽  
N. Graf
Keyword(s):  
Immune Responses ◽  
Early Life ◽  
Lymphoblastic Leukemia ◽  
Antibiotic Use ◽  
Intestinal Microbiome ◽  
Microbial Composition ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Host Immune Responses

AbstractAcute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas’ seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in Pax5 heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic “first hit”. Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.

scholarly journals KCTD15 is overexpressed in human childhood B-cell acute lymphoid leukemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Giovanni Smaldone ◽  
Giuliana Beneduce ◽  
Mariarosaria Incoronato ◽  
Katia Pane ◽  
Monica Franzese ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Pokeweed Mitogen ◽  
Pathological State ◽  
Lymphoid Leukemia ◽  
Continuous Cell Lines ◽  
Tetramerization Domain

AbstractLeukemic cells originate from the malignant transformation of undifferentiated myeloid/lymphoid hematopoietic progenitors normally residing in bone marrow. As the precise molecular mechanisms underlying this heterogeneous disease are yet to be disclosed, the identification and the validation of novel actors in leukemia is of extreme importance. Here, we show that KCTD15, a member of the emerging class of KCTD ((K)potassium Channel Tetramerization Domain containing) proteins, is strongly upregulated in patients affected by B-cell type acute lymphoblastic leukemia (B-ALL) and in continuous cell lines (RS4;11, REH, TOM-1, SEM) derived from this form of childhood leukemia. Interestingly, KCTD15 downregulation induces apoptosis and cell death suggesting that it has a role in cellular homeostasis and proliferation. In addition, stimulation of normal lymphocytes with the pokeweed mitogen leads to increased KCTD15 levels in a fashion comparable to those observed in proliferating leukemic cells. In this way, the role of KCTD15 is likely not confined to the B-ALL pathological state and extends to activation and proliferation of normal lymphocytes. Collectively, data here presented indicate that KCTD15 is an important and hitherto unidentified player in childhood lymphoid leukemia, and its study could open a new scenario for the identification of altered and still unknown molecular pathways in leukemia.

scholarly journals Expression Patterns of Coagulation Factor XIII Subunit A on Leukemic Lymphoblasts Correlate with Clinical Outcome and Genetic Subtypes in Childhood B-cell Progenitor Acute Lymphoblastic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2264
Author(s):  
Bettina Kárai ◽  
Katalin Gyurina ◽  
Anikó Ujfalusi ◽  
Łukasz Sędek ◽  
Gábor Barna ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Genetic Risk ◽  
Lymphoblastic Leukemia ◽  
Expression Patterns ◽  
Survival Rates ◽  
Coagulation Factor ◽  
Genetic Alterations ◽  
Subunit A

Background: Based on previous retrospective results, we investigated the association of coagulation FXIII subunit A (FXIII-A) expression pattern on survival and correlations with known prognostic factors of B-cell progenitor (BCP) childhood acute lymphoblastic leukemia (ALL) as a pilot study of the prospective multi-center BFM ALL-IC 2009 clinical trial. Methods: The study included four national centers (n = 408). Immunophenotyping by flow cytometry and cytogenetic analysis were performed by standard methods. Copy number alteration was studied in a subset of patients (n = 59). Survival rates were estimated by Kaplan-Meier analysis. Correlations between FXIII-A expression patterns and risk factors were investigated with Cox and logistic regression models. Results: Three different patterns of FXIII-A expression were observed: negative (<20%), dim (20–79%), and bright (≥80%). The FXIII-A dim expression group had significantly higher 5-year event-free survival (EFS) (93%) than the FXIII-A negative (70%) and FXIII-A bright (61%) groups. Distribution of intermediate genetic risk categories and the “B-other” genetic subgroup differed significantly between the FXIII-A positive and negative groups. Multivariate logistic regression confirmed independent association between the FXIII-A negative expression characteristics and the prevalence of intermediate genetic risk group. Conclusions: FXIII-A negativity is associated with dismal survival in children with BCP-ALL and is an indicator for the presence of unfavorable genetic alterations.

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