Special Issue "Leukemia"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2012)

Special Issue Editor

Guest Editor
Dr. Charles H. Lawrie

Lymphoid Malignancy Research Group, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
Website | E-Mail
Interests: cancer; lymphoma; leukemia; microarray; microRNA; biomarkers; non-coding RNA

Special Issue Information

Dear Colleagues,

Leukemia (leukaemia- British spelling) is a malignancy of the blood originating from immature leukocytes (lymphoid and myeloid). It is the most common form of childhood cancer (~1/3 of cases) and accounts for >44,000 new diagnoses and >22,000 mortalities annually in the US alone. Recent advances in both laboratory and clinic continue to improve the outcome for patients. This special edition of Cancers gives an opportunity to describe recent original research in the field of leukemia, the development or application of new platforms or insights, and/or reviews of the field. We are particularly interested in genomics, leukemia stem cell research, novel therapeutics, epidemiological studies and new biomarker studies. If you would like to discuss an idea for a paper before committing please contact the guest editor.

Dr. Charles Lawrie
Guest Editor

Keywords

  • acute lymphoblastic leukemia (ALL)
  • chronic lymphocytic leukemia (CLL)
  • acute myelogenous leukemia (AML)
  • chronic myelogenous leukemia (CML)
  • hairy cell leukemia (HCL)
  • T-cell prolymphocytic leukemia (T-PLL)
  • large granular lymphocytic leukemia
  • adult T-cell leukemia
  • human T-lymphotropic virus (HTLV)

Published Papers (7 papers)

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Research

Jump to: Review

Open AccessArticle A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)
Cancers 2013, 5(1), 281-295; doi:10.3390/cancers5010281
Received: 31 January 2013 / Revised: 28 February 2013 / Accepted: 4 March 2013 / Published: 11 March 2013
Cited by 3 | PDF Full-text (884 KB) | HTML Full-text | XML Full-text
Abstract
The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ
[...] Read more.
The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting. Full article
(This article belongs to the Special Issue Leukemia)
Open AccessArticle Do Non-Genomically Encoded Fusion Transcripts Cause Recurrent Chromosomal Translocations?
Cancers 2012, 4(4), 1036-1049; doi:10.3390/cancers4041036
Received: 26 July 2012 / Revised: 14 September 2012 / Accepted: 9 October 2012 / Published: 18 October 2012
Cited by 3 | PDF Full-text (733 KB) | HTML Full-text | XML Full-text
Abstract
We among others have recently demonstrated that normal cells produce “fusion mRNAs”. These fusion mRNAs do not derive from rearranged genomic loci, but rather they are derived from “early-terminated transcripts” (ETTs). Premature transcriptional termination takes place in intronic sequences that belong to “breakpoint
[...] Read more.
We among others have recently demonstrated that normal cells produce “fusion mRNAs”. These fusion mRNAs do not derive from rearranged genomic loci, but rather they are derived from “early-terminated transcripts” (ETTs). Premature transcriptional termination takes place in intronic sequences that belong to “breakpoint cluster regions”. One important property of ETTs is that they exhibit an unsaturated splice donor site. This results in: (1) splicing to “cryptic exons” present in the final intron; (2) Splicing to another transcript of the same gene (intragenic trans-splicing), resulting in “exon repetitions”; (3) splicing to a transcript of another gene (intergenic trans-splicing), leading to “non-genomically encoded fusion transcripts” (NGEFTs). These NGEFTs bear the potential risk to influence DNA repair processes, since they share identical nucleotides with their DNA of origin, and thus, could be used as “guidance RNA” for DNA repair processes. Here, we present experimental data about four other genes. Three of them are associated with hemato-malignancies (ETV6, NUP98 and RUNX1), while one is associated with solid tumors (EWSR1). Our results demonstrate that all genes investigated so far (MLL, AF4, AF9, ENL, ELL, ETV6, NUP98, RUNX1 and EWSR1) display ETTs and produce transpliced mRNA species, indicating that this is a genuine property of translocating genes. Full article
(This article belongs to the Special Issue Leukemia)
Open AccessArticle Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL
Cancers 2012, 4(4), 1050-1066; doi:10.3390/cancers4041050
Received: 26 July 2012 / Revised: 2 October 2012 / Accepted: 9 October 2012 / Published: 18 October 2012
PDF Full-text (968 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead
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Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression. Full article
(This article belongs to the Special Issue Leukemia)
Open AccessArticle Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α
Cancers 2012, 4(3), 743-762; doi:10.3390/cancers4030743
Received: 1 June 2012 / Revised: 11 July 2012 / Accepted: 13 July 2012 / Published: 25 July 2012
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Abstract
Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor
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Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML. Full article
(This article belongs to the Special Issue Leukemia)
Open AccessArticle Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission
Cancers 2012, 4(2), 601-617; doi:10.3390/cancers4020601
Received: 17 May 2012 / Revised: 13 June 2012 / Accepted: 14 June 2012 / Published: 20 June 2012
Cited by 3 | PDF Full-text (242 KB) | HTML Full-text | XML Full-text
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with
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Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS. Full article
(This article belongs to the Special Issue Leukemia)

Review

Jump to: Research

Open AccessReview The Development of Novel Therapies for the Treatment of Acute Myeloid Leukemia (AML)
Cancers 2012, 4(4), 1161-1179; doi:10.3390/cancers4041161
Received: 22 August 2012 / Revised: 29 September 2012 / Accepted: 17 October 2012 / Published: 2 November 2012
Cited by 3 | PDF Full-text (422 KB) | HTML Full-text | XML Full-text
Abstract
Acute myeloid leukemia (AML) is nearly always a fatal malignancy. For the past 40 years, the standard of care remains a combination of cytarabine and an anthracycline known as 7 + 3. This treatment regimen is troubled by both low survival rates (10%
[...] Read more.
Acute myeloid leukemia (AML) is nearly always a fatal malignancy. For the past 40 years, the standard of care remains a combination of cytarabine and an anthracycline known as 7 + 3. This treatment regimen is troubled by both low survival rates (10% at 5 years) and deaths due to toxicity. Substantial new laboratory findings over the past decade have identified many cellular pathways that contribute to leukemogenesis. These studies have led to the development of novel agents designed to target these pathways. Here we discuss the molecular underpinnings and clinical benefits of these novel treatment strategies. Most importantly these studies demonstrate that clinical response is best achieved by stratifying each patient based on a detailed understanding of their molecular abnormalities. Full article
(This article belongs to the Special Issue Leukemia)
Open AccessReview Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
Cancers 2012, 4(3), 904-944; doi:10.3390/cancers4030904
Received: 2 August 2012 / Revised: 31 August 2012 / Accepted: 4 September 2012 / Published: 10 September 2012
Cited by 5 | PDF Full-text (421 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues
[...] Read more.
Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis. Full article
(This article belongs to the Special Issue Leukemia)

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