scholarly journals Differential mRNA and long noncoding RNA expression profiles in pediatric B-cell acute lymphoblastic leukemia patients

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Jing Xia ◽  
Mengjie Wang ◽  
Yi Zhu ◽  
Chaozhi Bu ◽  
Tianyu Li
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Data Availability ◽  
Differentially Expressed ◽  
Kegg Analysis ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides (nt) that are involved in the pathogenesis and development of various cancers including B cell acute lymphoblastic leukemia (B–ALL). To determine the potential roles of lncRNAs involved in pathogenesis of B-ALL, we analyzed the expression profile of lncRNAs and mRNAs in B-ALL, respectively, and constructed lncRNAs/mRNAs interaction network. Methods We performed RNA sequencing of 10 non-leukemic blood disease donors and 10 B-ALL patients for Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Interactions among mRNAs were predicted using the STRING database. Quantitative real time PCR (qRT-PCR) was performed to verify the RNA-seq data of lncRNAs and mRNAs. Potential functions of subtype-specific lncRNAs were determined by using coexpression-based analysis on distally (trans-pattern) located protein-coding genes. Results A total of 1813 differentially expressed transcripts (DETs) and 2203 lncRNAs were identified. Moreover, 10 dysregulated lncRNAs and 10 mRNAs were randomly selected, and further assessed by RT-qPCR in vitro. Go and KEGG analysis demonstrated that the differentially expressed mRNAs were most closely associated with myeloid leukocyte activation and in transcriptional misregulation in cancer, respectively. In addition, co-expression analysis demonstrated that these lncRNAs, including MSTRG.27994.3, MSTRG.21740.1, ENST00000456341, MSTRG.14224.1 and MSTRG.20153.1, may mediate the pathogenesis and development of B-ALL via lncRNA-mRNA network interactions. Conclusions These results showed that several mRNAs and lncRNAs are aberrantly expressed in the bone marrow of B-ALL patients and play potential roles in B-ALL development, and be useful for diagnostic and/or prognostic purposes in pediatric B–ALL. Data availability The datasets used during our study are available through HARVARD Dataverse Persistent ID doi:10.7910/DVN/LK9T4Z.

scholarly journals Expression of ZNF695 Transcript Variants in Childhood B-Cell Acute Lymphoblastic Leukemia

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 716 ◽  
Author(s):  
Rosa ◽  
Villegas-Ruíz ◽  
Caballero-Palacios ◽  
Pérez-López ◽  
Murata ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Alternative Transcript ◽  
Human Transcriptome ◽  
Transcript Variants ◽  
Cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia is the most commonly diagnosed childhood malignancy worldwide; more than 50% of these cases are diagnosed in Mexico. Although the five-year survival rate is >80%, 30% of patients experience relapse with poor prognosis. Cancer-associated gene expression profiles have been identified in several malignancies, and some transcripts have been used to predict disease prognosis. The human transcriptome is incompletely elucidated; moreover, more than 80% of transcripts can be processed via alternative splicing (AS), which increases transcript and protein diversity. The human transcriptome is divided; coding RNA accounts for 2%, and the remaining 98% is noncoding RNA. Noncoding RNA can undergo AS, promoting the diversity of noncoding transcripts. We designed specific primers to amplify previously reported alternative transcript variants of ZNF695 and showed that six ZNF695 transcript variants are co-expressed in cancer cell lines. The amplicons were sequenced and identified. Additionally, we analyzed the expression of these six transcript variants in bone marrow from B-cell acute lymphoblastic leukemia patients and observed that ZNF695 transcript variants one and three were the predominant variants expressed in leukemia. Moreover, our results showed the co-expression of coding and long noncoding RNA. Finally, we observed that long noncoding RNA ZNF695 expression predicted survival rates.

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

Abstract In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

scholarly journals ALLSorts: a RNA-Seq classifier for B-Cell Acute Lymphoblastic Leukemia.

2021 ◽  
Author(s):  
Breon M Schmidt ◽  
Lauren M Brown ◽  
Georgina L Ryland ◽  
Andrew Lonsdale ◽  
Hansen J Kosasih ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Learning Algorithm ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Supervised Machine Learning ◽  
World Health ◽  
Rna Seq ◽  
Cancer Subtypes ◽  
Cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Subtypes within B-ALL are distinguished by characteristic structural variants and mutations, which in some instances strongly correlate with responses to treatment. The World Health Organisation (WHO) recognises seven distinct classifications, or subtypes, as of 2016. However, recent studies have demonstrated that B-ALL can be segmented into 23 subtypes based on a combination of genomic features and gene expression profiles. A method to identify a patient's subtype would have clear clinical utility. Despite this, no publically available classification methods using RNA-Seq exist for this purpose. Here we present ALLSorts: a publicly available method that uses RNA-Seq data to classify B-ALL samples to 18 known subtypes and five meta-subtypes. ALLSorts is the result of a hierarchical supervised machine learning algorithm applied to a training set of 1223 B-ALL samples aggregated from multiple cohorts. Validation revealed that ALLSorts can accurately attribute samples to subtypes and can attribute multiple subtypes to a sample. Furthermore, when applied to both paediatric and adult cohorts, ALLSorts was able to classify previously undefined samples into subtypes. ALLSorts is available and documented on GitHub (https://github.com/Oshlack/AllSorts/).

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

scholarly journals Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages

2015 ◽  
Vol 112 (13) ◽  
pp. 4074-4079 ◽  
Author(s):  
James Scott McClellan ◽  
Christopher Dove ◽  
Andrew J. Gentles ◽  
Christine E. Ryan ◽  
Ravindra Majeti
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Lineage Reprogramming ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Differentiation Block ◽  
Factor C ◽  
And Function

BCR–ABL1+ precursor B-cell acute lymphoblastic leukemia (BCR–ABL1+ B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR–ABL1+ B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR–ABL1+ B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14+ monocytes/macrophages in BCR–ABL1+ B-ALL patient samples that possess the BCR–ABL1+ translocation and clonally recombined VDJ regions.

Rac2 GTPase Activation Is Necessary for Development of p190-BCR-ABL-Induced B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3790-3790
Author(s):  
Abel Sanchez-Aguilera ◽  
Ami tava Sengupta ◽  
Joseph P Mastin ◽  
Kyung H Chang ◽  
David A Williams ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Rho Gtpases ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The fusion gene BCR-ABL, resulting from t(9;22) reciprocal chromosomal translocations, encodes a constitutively active tyrosine kinase. Two different isoforms of BCR-ABL, p190 and p210, are associated to two completely different diseases. In the tyrosine kinase inhibitor (TKI) era, while p210-BCR-ABL-induced CML is highly responsive to TKI, p190-BCR-ABL still induces a poor prognosis B-cell acute lymphoblastic leukemia (B-ALL). The only difference between these two forms of BCR-ABL is the existence of a DH/Cdc24/PH domain in p210-BCR-ABL, which acts as a guanine nucleotide exchange factor (GEF) able to activate Rho GTPases. Rac is a subfamily of Rho GTPases with regulatory activity on hematopoietic stem cell and progenitor (HSC/P) functions. We have previously shown that Rac2 and further the combination of Rac1 and Rac2 mediate downstream signals in p210 BCR-ABL-induced myeloproliferation (Thomas EK, et al., Cancer Cell, 2007). Interestingly, despite the absence of a GEF domain in p190-BCR-ABL, Rac is activated, suggesting the activation of other GEF(s). Here we have analyzed whether Vav and Rac family members are involved in p190-BCR-ABL-induced B-ALL. We have used a combination of in vitro (Ba/F3 pro-B cells transduced with p190 or p210 BCR-ABL) and in vivo (murine transduction-transplantation model of p190 BCR-ABL-induced B-ALL) approaches. In Ba/F3 cells, both p190 BCR-ABL and p210 BCR-ABL activated Rac and the Rac effector p21 activated kinase (PAK), and their proliferation and survival appeared severely decreased in response to the Rac activation inhibitor NSC23766. Stat3, Stat5 and Jnk, but not ERK, p38 or NF-kB, were constitutively hyperactivated in p190 BCRABL-expressing Ba/F3 cells and primary murine B-ALL cells. Intracellular flow cytometry analysis demonstrated that Stat5 was specifically activated in the pro/pre-B leukemic cell population, compared to normal B cells. In the murine model of B-ALL, loss of Rac2, but not Rac3, prolonged survival and impaired leukemia development. Like in Ba/F3 cells, primary B-CFU and outgrowth in Witte-Whitlock assays of leukemic primary cells from mice was severely decreased by the addition of NSC23766 to the culture. Although Vav was activated by both p190- and p210-BCR-ABL, since NSC23766 does not block the activation by Vav1, we hypothesized that other GEFs were involved. Indeed, the loss of Vav1 or even combined loss of Vav1 and Vav2 did not impair BCR-ABL-mediated lymphoid leukemogenesis in vivo. Vav3, another member in the Vav family which uses a different mechanism of activation of Rac GTPases was a likely candidate. In fact, loss of Vav3 alone was able to significantly prolong the survival and attenuate development of p190 BCR-ABL-driven B-ALL. In conclusion, the results of this study indicate that Rac activation is necessary for the development of B-ALL induced by p190-BCR-ABL in vitro and in vivo, and validate a new signaling pathway as a therapeutic target for BCR-ABL-induced B-ALL.

scholarly journals PF161 THIOREDOXIN SYSTEM INHIBITORS ARE EFFECTIVE AGAINST B CELL ACUTE LYMPHOBLASTIC LEUKEMIA IN VITRO AND IN VIVO

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 32-33
Author(s):  
K. Fidyt ◽  
A. Pastorczak ◽  
A. Goral ◽  
A. Muchowicz ◽  
L. Komorowski ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Thioredoxin System ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

Blood ◽  
2020 ◽  
Vol 136 (13) ◽  
pp. 1520-1534 ◽  
Author(s):  
Chunhua Song ◽  
Zheng Ge ◽  
Yali Ding ◽  
Bi-Hua Tan ◽  
Dhimant Desai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Specific Inhibitor ◽  
Therapeutic Effects ◽  
Loss Of Function ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Resistance To Doxorubicin

Abstract High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS’ function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

scholarly journals Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche

2020 ◽  
Vol 6 (44) ◽  
pp. eaba5536
Author(s):  
Chao Ma ◽  
Matthew T. Witkowski ◽  
Jacob Harris ◽  
Igor Dolgalev ◽  
Sheetal Sreeram ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Chemotherapy Resistance ◽  
Patient Specific ◽  
Bone Marrow Niche ◽  
Cell Acute Lymphoblastic Leukemia

B cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemoprotective leukemic BM “niches,” facilitating chemoresistance and, ultimately, disease relapse. However, the ability to dissect these evolving, heterogeneous interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Here, we demonstrated an in vitro organotypic “leukemia-on-a-chip” model to emulate the in vivo B-ALL BM pathology and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance. We revealed the heterogeneous chemoresistance mechanisms across various B-ALL cell lines and patient-derived samples. We showed that the leukemic perivascular, endosteal, and hematopoietic niche-derived factors maintain B-ALL survival and quiescence (e.g., CXCL12 cytokine signal, VCAM-1/OPN adhesive signals, and enhanced downstream leukemia-intrinsic NF-κB pathway). Furthermore, we demonstrated the preclinical use of our model to test niche-cotargeting regimens, which may translate to patient-specific therapy screening and response prediction.

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