International Journal of Molecular Sciences

Research

14 pages, 3835 KiB

Open AccessArticle

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2

by Elanora Dovat, Chunhua Song, Tommy Hu, Mohammad Atiqur Rahman, Pavan Kumar Dhanyamraju, Morgann Klink, Daniel Bogush, Mario Soliman, Shriya Kane, Mary McGrath, Yali Ding, Dhimant Desai, Arati Sharma and Chandrika Gowda

Int. J. Mol. Sci. 2021, 22(2), 819; https://doi.org/10.3390/ijms22020819 - 15 Jan 2021

Cited by 5 | Viewed by 3889

Abstract

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes [...] Read more.

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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20 pages, 6128 KiB

Open AccessArticle

Regulation of Small GTPase Rab20 by Ikaros in B-Cell Acute Lymphoblastic Leukemia

by Jonathon L Payne, Chunhua Song, Yali Ding, Pavan Kumar Dhanyamraju, Yevgeniya Bamme, Joseph W Schramm, Dhimant Desai, Arati Sharma, Chandrika Gowda and Sinisa Dovat

Int. J. Mol. Sci. 2020, 21(5), 1718; https://doi.org/10.3390/ijms21051718 - 3 Mar 2020

Cited by 5 | Viewed by 3745

Abstract

Ikaros is a DNA-binding protein that regulates gene expression and functions as a tumor suppressor in B-cell acute lymphoblastic leukemia (B-ALL). The full cohort of Ikaros target genes have yet to be identified. Here, we demonstrate that Ikaros directly regulates expression of the [...] Read more.

Ikaros is a DNA-binding protein that regulates gene expression and functions as a tumor suppressor in B-cell acute lymphoblastic leukemia (B-ALL). The full cohort of Ikaros target genes have yet to be identified. Here, we demonstrate that Ikaros directly regulates expression of the small GTPase, Rab20. Using ChIP-seq and qChIP we assessed Ikaros binding and the epigenetic signature at the RAB20 promoter. Expression of Ikaros, CK2, and RAB20 was determined by qRT-PCR. Overexpression of Ikaros was achieved by retroviral transduction, whereas shRNA was used to knockdown Ikaros and CK2. Regulation of transcription from the RAB20 promoter was analyzed by luciferase reporter assay. The results showed that Ikaros binds the RAB20 promoter in B-ALL. Gain-of-function and loss-of-function experiments demonstrated that Ikaros represses RAB20 transcription via chromatin remodeling. Phosphorylation by CK2 kinase reduces Ikaros’ affinity toward the RAB20 promoter and abolishes its ability to repress RAB20 transcription. Dephosphorylation by PP1 phosphatase enhances both Ikaros’ DNA-binding affinity toward the RAB20 promoter and RAB20 repression. In conclusion, the results demonstrated opposing effects of CK2 and PP1 on expression of Rab20 via control of Ikaros’ activity as a transcriptional regulator. A novel regulatory signaling network in B-cell leukemia that involves CK2, PP1, Ikaros, and Rab20 is identified. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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Review

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17 pages, 1693 KiB

Open AccessReview

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

by Parveen Shiraz, Kimberly J. Payne and Lori Muffly

Int. J. Mol. Sci. 2020, 21(6), 2193; https://doi.org/10.3390/ijms21062193 - 22 Mar 2020

Cited by 29 | Viewed by 4795

Abstract

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, [...] Read more.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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16 pages, 944 KiB

Open AccessReview

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

by Pavan Kumar Dhanyamraju, Soumya Iyer, Gayle Smink, Yevgeniya Bamme, Preeti Bhadauria, Jonathon L Payne, Elanora Dovat, Morgann Klink and Yali Ding

Int. J. Mol. Sci. 2020, 21(4), 1377; https://doi.org/10.3390/ijms21041377 - 18 Feb 2020

Cited by 9 | Viewed by 4263

Abstract

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide [...] Read more.

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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18 pages, 1116 KiB

Open AccessReview

The Role Played by Wnt/β-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia

by Francesca Chiarini, Francesca Paganelli, Alberto M. Martelli and Camilla Evangelisti

Int. J. Mol. Sci. 2020, 21(3), 1098; https://doi.org/10.3390/ijms21031098 - 7 Feb 2020

Cited by 37 | Viewed by 9292

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of [...] Read more.

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/β-catenin in hematopoietic malignancies and provides information on the current status of Wnt/β-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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15 pages, 708 KiB

Open AccessReview

Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

by Aaron Kruse, Nour Abdel-Azim, Hye Na Kim, Yongsheng Ruan, Valerie Phan, Heather Ogana, William Wang, Rachel Lee, Eun Ji Gang, Sajad Khazal and Yong-Mi Kim

Int. J. Mol. Sci. 2020, 21(3), 1054; https://doi.org/10.3390/ijms21031054 - 5 Feb 2020

Cited by 61 | Viewed by 9113

Abstract

Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new [...] Read more.

Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new diagnostic platforms, including next-generation sequencing (NGS), has introduced significant advances in the sensitivity of MRD diagnostics. Here, we review current methods to diagnose MRD through phenotypic marker patterns or differential gene patterns through analysis by flow cytometry (FCM), polymerase chain reaction (PCR), real-time quantitative polymerase chain reaction (RQ-PCR), reverse transcription polymerase chain reaction (RT-PCR) or NGS. Future advances in clinical procedures will be molded by practical feasibility and patient needs regarding greater diagnostic sensitivity. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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20 pages, 266 KiB

Open AccessReview

Tackling Acute Lymphoblastic Leukemia—One Fish at a Time

by Arpan A. Sinha, Gilseung Park and J. Kimble Frazer

Int. J. Mol. Sci. 2019, 20(21), 5313; https://doi.org/10.3390/ijms20215313 - 25 Oct 2019

Cited by 3 | Viewed by 3465

Abstract

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more [...] Read more.

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer’s genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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Graphical abstract

22 pages, 304 KiB

Open AccessReview

Next-Generation Sequencing in Acute Lymphoblastic Leukemia

by Nicoletta Coccaro, Luisa Anelli, Antonella Zagaria, Giorgina Specchia and Francesco Albano

Int. J. Mol. Sci. 2019, 20(12), 2929; https://doi.org/10.3390/ijms20122929 - 15 Jun 2019

Cited by 55 | Viewed by 9742

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for about a quarter of adult acute leukemias, and features different outcomes depending on the age of onset. Improvements in ALL genomic analysis achieved thanks to the implementation of next-generation sequencing [...] Read more.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for about a quarter of adult acute leukemias, and features different outcomes depending on the age of onset. Improvements in ALL genomic analysis achieved thanks to the implementation of next-generation sequencing (NGS) have led to the recent discovery of several novel molecular entities and to a deeper understanding of the existing ones. The purpose of our review is to report the most recent discoveries obtained by NGS studies for ALL diagnosis, risk stratification, and treatment planning. We also report the first efforts at NGS use for minimal residual disease (MRD) assessment, and early studies on the application of third generation sequencing in cancer research. Lastly, we consider the need for the integration of NGS analyses in clinical practice for genomic patients profiling from the personalized medicine perspective. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

Other

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8 pages, 698 KiB

Open AccessBrief Report

SYK Targeting Represents a Potential Therapeutic Option for Relapsed Resistant Pediatric ETV6-RUNX1 B-Acute Lymphoblastic Leukemia Patients

by Valentina Serafin, Elena Porcù, Giuliana Cortese, Elena Mariotto, Giulia Veltri, Silvia Bresolin, Giuseppe Basso and Benedetta Accordi

Int. J. Mol. Sci. 2019, 20(24), 6175; https://doi.org/10.3390/ijms20246175 - 7 Dec 2019

Cited by 6 | Viewed by 2529

Abstract

The presence of the chromosomal rearrangement t(12;21)(ETV6-RUNX1) in childhood B-acute lymphoblastic leukemia (B-ALL) is an independent predictor of favorable prognosis, however relapses still occur many years later after stopping therapy, and patients often display resistance to current treatments. Since spleen tyrosine [...] Read more.

The presence of the chromosomal rearrangement t(12;21)(ETV6-RUNX1) in childhood B-acute lymphoblastic leukemia (B-ALL) is an independent predictor of favorable prognosis, however relapses still occur many years later after stopping therapy, and patients often display resistance to current treatments. Since spleen tyrosine kinase (SYK), a cytosolic nonreceptor tyrosine kinase interacting with immune receptors, has been previously associated with malignant transformation and cancer cell proliferation, we aimed to assess its role in ETV6-RUNX1 cell survival and prognosis. We evaluated the effects on cell survival of three SYK inhibitors and showed that all of them, in particular entospletinib, are able to induce cell death and enhance the efficacy of conventional chemotherapeutics. By using reverse phase protein arrays we next revealed that activated SYK is upregulated at diagnosis in pediatric ETV6-RUNX1 patients who will experience relapse, and, importantly, hyperactivation is maintained at a high level also at relapse occurrence. We thus treated primary cells from patients both at diagnosis and relapse with the combination entospletinib + chemotherapeutics and observed that SYK inhibition is able to sensitize resistant primary cells to conventional drugs. Entospletinib could thus represent a new therapeutic option supporting conventional chemotherapy for relapsed ETV6-RUNX1 patients, and these evidences encourage further studies on SYK for treatment of other relapsed resistant acute lymphoblastic leukemia (ALL) subgroups. Full article

(This article belongs to the Special Issue Molecular Research on Acute Lymphoblastic Leukemia)

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