Publications by authors named "Anthony M Ford"

23 Publications

  • Page 1 of 1

The Role of MicroRNA in Paediatric Acute Lymphoblastic Leukaemia: Challenges for Diagnosis and Therapy.

J Oncol 2019 13;2019:8941471. Epub 2019 Oct 13.

Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Although the overall survival of children with ALL is now more than 90%, leukaemia remains one of the leading causes of death from disease. In developed countries, the overall survival of patients with ALL has increased to more than 80%; however, those children cured from ALL still show a significant risk of short- and long-term complications as a consequence of their treatment. Accordingly, there is a need not only to develop new methods of diagnosis and prognosis but also to provide patients with less toxic therapies. MicroRNAs (miRNAs) are small ribonucleic acids (RNA), usually without coding potential, that regulate gene expression by directing their target messenger RNAs (mRNAs) for degradation or translational suppression. In paediatric ALL, several miRNAs have been observed to be overexpressed or underexpressed in patient cohorts compared to healthy individuals, while numerous studies have identified specific miRNAs that can be used as biomarkers to diagnose ALL, classify it into subgroups, and predict prognosis. Likewise, a variety of miRNAs identify as candidate targets for treatment, although there are numerous obstacles to overcome before their clinical use in patients. Here, we summarise the roles played by different miRNAs in childhood leukaemia, focussing primarily on their use as diagnostic tools and potential therapeutic targets, as well as a role in predicting treatment outcome. Finally, we discuss the potential roles of miRNA in immunotherapy and the novel contributions made by gut miRNAs to regulation of the host microbiome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8941471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815594PMC
October 2019

Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.

Mol Cell 2019 05 21;74(3):584-597.e9. Epub 2019 Mar 21.

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address:

V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509286PMC
May 2019

Origins of STIL-TAL1 fusion genes in children who later developed paediatric T-cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots.

Pediatr Blood Cancer 2018 11 3;65(11):e27310. Epub 2018 Jul 3.

Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.

SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27310DOI Listing
November 2018

The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.

Leukemia 2018 09 20;32(9):1984-1993. Epub 2018 Mar 20.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-018-0046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127084PMC
September 2018

The role of RAS mutations in MLL-rearranged leukaemia: A path to intervention?

Biochim Biophys Acta Rev Cancer 2017 Dec 19;1868(2):521-526. Epub 2017 Oct 19.

Molecular Cancer Study Group, Research Centre, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, 2° floor, Rio de Janeiro, RJ 20231050, Brazil. Electronic address:

Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results. In this context, this mini-review summarizes the available data surrounding MLL-r infant ALL with RAS mutation in relation to other well-known features of this intriguing disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbcan.2017.10.005DOI Listing
December 2017

ETV6-RUNX1 Acute Lymphoblastic Leukaemia in Identical Twins.

Adv Exp Med Biol 2017 ;962:217-228

Centre for Evolution and Cancer, The Institute of Cancer Research, London, SM2 5NG, UK.

Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-981-10-3233-2_14DOI Listing
September 2017

Distinctive genotypes in infants with T-cell acute lymphoblastic leukaemia.

Br J Haematol 2015 Nov 24;171(4):574-84. Epub 2015 Jul 24.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic deletion on chromosome 3. These losses result in the complete deletion of MLF1 and have not previously been described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14·1-11q23·2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations; in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. KMT2A rearrangements (KMT2A-r) were detected in three out of 13 cases. For three patients, mutations and copy number alterations (including deletion of PTEN) could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates that iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.13613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737125PMC
November 2015

Concordant B-cell precursor acute lymphoblastic leukemia in non-twinned siblings.

Blood Cells Mol Dis 2015 Jan 20;54(1):110-5. Epub 2014 Aug 20.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.

Associating the risk of childhood acute lymphoblastic leukemia (ALL) with genetic predisposition is still a challenge. Here, we discuss two non-twinned sibs (girl and boy) diagnosed with B-cell precursor (BCP-ALL) and ETV6-RUNX1. BCP-ALL clinical onset occurred 10months apart from each diagnosis. One child is alive in complete continuous remission, whereas, the other relapsed and evolved to death with resistance to ALL treatment. Despite the fact that BCP-ALL with ETV6-RUNX1 usually results in a very good prognosis, the sibs experienced divergent outcomes; a remarkable difference in one child that presented a more aggressive disease was higher leukocytosis associated with IKZF1 deletion. The familial history of cancer and genetic susceptibility was explored. The sibs were absolutely identical in all 17 loci of genes tested; GSTM1, GSTT1, NQO1, TP53, and TP63 were wild-type, whereas at least one copy of the variant allele for IKZF1, ARID5B, PTPRJ and CEBPE was present. The familial pattern of ETV6 was tested by the 12p microsatellite analysis and demonstrated that deletions occurred in one child but not the other, while heterozygous patterns were found in the parents. Altogether, our data suggest that genetic predisposition aligned with chance haa an additive effect in BCP-ALL outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2014.07.011DOI Listing
January 2015

RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.

Nat Genet 2014 Feb 12;46(2):116-25. Epub 2014 Jan 12.

Centro Ricerca Tettamanti, Hospital San Gerardo, Monza, Italy.

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.2874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960636PMC
February 2014

Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia.

Blood 2011 Nov 29;118(20):5559-64. Epub 2011 Sep 29.

Centro Ricerca Tettamanti, Clinica Pediatrica, Universita di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.

The timing and developmental sequence of events for BCR-ABL1(+) acute lymphoblastic leukemia (ALL), usually associated with IKAROS (IKZF1) deletions, are unknown. We assessed the status of BCR-ABL1 and IKZF1 genes in 2 pairs of monozygotic twins, one pair concordant, the other discordant for Philadelphia chromosome positive (Ph(+)) ALL. The twin pair concordant for ALL shared identical BCR-ABL1 genomic sequence indicative of monoclonal, in utero origin. One twin had IKZF1 deletion and died after transplantation. The other twin had hyperdiploidy, no IKZF1 deletion, and is still in remission 8 years after transplantation. In the twin pair discordant for ALL, neonatal blood spots from both twins harbored the same clonotypic BCR-ABL1 sequence. Low level BCR-ABL1(+) cells were present in the healthy co-twin but lacked the IKZF1 deletion present in the other twin's leukemic cells. The twin with ALL relapsed and died after transplantation. The co-twin remains healthy and leukemia free. These data show that in childhood Ph(+) ALL, BCR-ABL1 gene fusion can be a prenatal and possibly initiating genetic event. In the absence of additional, secondary changes, the leukemic clone remains clinically silent. IKZF1 is a secondary and probable postnatal mutation in these cases, and as a recurrent but alternative copy number change is associated with poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-07-366542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217357PMC
November 2011

ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor.

Blood 2011 Nov 7;118(18):4910-8. Epub 2011 Sep 7.

Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, UK.

ETV6-RUNX1 gene fusion is usually an early, prenatal event in childhood acute lymphoblastic leukemia (ALL). Transformation results in the generation of a persistent (> 14 years) preleukemic clone, which postnatally converts to ALL after the acquisition of necessary secondary genetic alterations. Many cancer cells show some expression of the erythropoietin receptor (EPOR) gene, although the "functionality" of any EPOR complexes and their relevant signaling pathways in nonerythroid cells has not been validated. EPOR mRNA is selectively and ectopically expressed in ETV6-RUNX1(+) ALL, but the presence of a functional EPOR on the cell surface and its role in leukemogenesis driven by ETV6-RUNX1 remains to be identified. Here, we show that ETV6-RUNX1 directly binds the EPOR promoter and that expression of ETV6-RUNX1 alone in normal pre-B cells is sufficient to activate EPOR transcription. We further reveal that murine and human ETV6-RUNX1(+) cells expressing EPOR mRNA have EPO ligand binding activity that correlates with an increased cell survival through activation of the JAK2-STAT5 pathway and up-regulation of antiapoptotic BCL-XL. These data support the contention that ETV6-RUNX1 directly activates ectopic expression of a functional EPOR and provides cell survival signals that may contribute critically to persistence of covert premalignant clones in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-05-354266DOI Listing
November 2011

Fusion genes in cord blood.

Blood 2011 Jan;117(1):369-70; author reply 370-1

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2010-09-309351DOI Listing
January 2011

Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.

Blood 2010 Apr 8;115(17):3553-8. Epub 2010 Jan 8.

Section of Haemato-Oncology, The Institute of Cancer Research, Surrey, UK.

Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2009-10-251413DOI Listing
April 2010

Immunologically silent cancer clone transmission from mother to offspring.

Proc Natl Acad Sci U S A 2009 Oct 12;106(42):17882-5. Epub 2009 Oct 12.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138519, Japan.

Rare cases of possible materno-fetal transmission of cancer have been recorded over the past 100 years but evidence for a shared cancer clone has been very limited. We provide genetic evidence for mother to offspring transmission, in utero, of a leukemic cell clone. Maternal and infant cancer clones shared the same unique BCR-ABL1 genomic fusion sequence, indicating a shared, single-cell origin. Microsatellite markers in the infant cancer were all of maternal origin. Additionally, the infant, maternally-derived cancer cells had a major deletion on one copy of chromosome 6p that included deletion of HLA alleles that were not inherited by the infant (i.e., foreign to the infant), suggesting a possible mechanism for immune evasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0904658106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764945PMC
October 2009

The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.

J Clin Invest 2009 Apr 16;119(4):826-36. Epub 2009 Mar 16.

Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI36428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662549PMC
April 2009

Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.

Blood 2009 Jan 16;113(3):646-8. Epub 2008 Oct 16.

Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom.

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2008-08-170928DOI Listing
January 2009

Therapeutic opportunities and targets in childhood leukemia.

Clin Transl Oncol 2006 Aug;8(8):560-5

Section of Haemato-Oncology, Institute of Cancer Research, Sutton, United Kingdom.

Childhood leukemia is a common pediatric cancer in the developed world, the disease is biologically diverse and there is much discussion as to its causal mechanisms. Acute lymphoblastic leukemia (ALL) is the most common subtype and infants with ALL have a greatly increased risk of treatment failure. There are molecular and biological properties of leukemic cells that determine treatment outcome; these can usually be attributed to distinct genetic abnormalities that alter the normal proliferative and survival signals of hematopoietic cells. Experimental evidence for the existence of leukemic stem cells (LSC) has been obtained, and it is presumed that these cells arise from mutations in normal hematopoetic stem cells or progenitor cells, and they are difficult to eradicate. LSC seem to be surprisingly different from their normal counterparts and therefore are obvious new targets for drug therapy. Therapeutic concepts using monoclonal antibodies have substantially improved response rates in patients with malignant lymphomas and are currently being evaluated in other types of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12094-006-0061-5DOI Listing
August 2006

MLL translocations with concurrent 3' deletions: interpretation of FISH results.

Genes Chromosomes Cancer 2004 Nov;41(3):266-71

Leukaemia Research Fund Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom.

Rearrangements involving the MLL gene at 11q23 occur in a clinically relevant subgroup of patients with acute lymphoblastic leukemia (ALL) at all ages, and therefore their accurate identification at diagnosis is important. It has become commonplace to screen ALL patients for rearrangements of MLL using a dual-color fluorescence in situ hybridization (FISH) assay. We report on 12 ALL patients with an unusual FISH result consisting of the following signal pattern: one 5' green, no 3' red, and one/two fusion signals. This configuration is consistent with a MLL translocation and simultaneous deletion of 3' MLL-a well-established phenomenon-which has been interpreted as a positive result. G-banded and complementary metaphase FISH analyses confirmed an 11q23/MLL translocation in 8 of the 12 cases, whereas in one case, the identification of a del(11)(q23) was restricted to G-banded analysis only. In three cases, an MLL rearrangement was excluded by extensive FISH analysis and/or Southern blotting. In conclusion, the loss of the 3' MLL signal should not be assumed to be the result of a concurrent translocation and deletion event, and such aberrant FISH signal patterns should be investigated further by alternative methods for determining their MLL status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.20082DOI Listing
November 2004

TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia.

Clin Cancer Res 2004 Aug;10(16):5355-60

Leukemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, London, United Kingdom.

Purpose: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.

Experimental Design: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.

Results: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.

Conclusions: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-04-0584DOI Listing
August 2004

Pre-natal, clonal origin of acute lymphoblastic leukaemia in triplets.

Leuk Lymphoma 2003 Dec;44(12):2099-102

CLIP--Childhood Leukaemia Investigation, Prague, Czech Republic.

A unique case of ALL in three monozygotic triplets diagnosed at the age of 24, 27 and 37 months is described. Archived bone marrow smears were available for molecular analysis of immunoglobulin heavy chain (IGH) and IGK genes and T-cell receptor (TCR)-delta and gamma gene rearrangements. A shared IGH rearrangement was found in triplets "A" and "B", and an identical rearrangement of TCR-delta in triplets "B" and "C". These data suggest a common, monoclonal initiation of ALL in one of these three triplets, followed by dissemination of clonal progeny to the other twins via vascular anastomoses within the single, monochorionic placenta that they shared in utero. Differences in IGH rearrangements in diagnostic samples also indicates divergent subclonal evolution of the original "pre-leukaemic" clone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1042819031000123393DOI Listing
December 2003

Expression profile of wild-type ETV6 in childhood acute leukaemia.

Br J Haematol 2003 Jul;122(1):94-8

Children's Cancer Group, and Medical Oncology Unit, Cancer Research UK, St Bartholomew's and The London, Queen Mary School of Medicine and Dentistry, London, UK.

Comparative expression analysis of wild-typeETV6 in the disease state showed an absence of expression in ETV6-CBFA2 acute lymphoblastic leukaemia (ALL) when compared with non-ETV6-CBFA2 ALL and acute myeloid leukaemia. Fluorescent in-situ hybridization and loss of heterozygosity studies showed that 73% of the ETV6-CBFA2 samples had a fully or partially deleted second ETV6 allele, explaining the lack of wild-type expression in these patients. Although the second ETV6 allele was identified in the remaining patients, no ETV6 expression was detected. These observations support the hypothesis that loss of ETV6 expression is a critical secondary event for leukaemogenesis in ETV6-CBFA2 ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1046/j.1365-2141.2003.04399.xDOI Listing
July 2003

Leukemia in twins: lessons in natural history.

Blood 2003 Oct 5;102(7):2321-33. Epub 2003 Jun 5.

Leukemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Rd, London SW3 6JB, United Kingdom.

Identical infant twins with concordant leukemia were first described in 1882, and since that time many such pairs of infants and older children have been described. It has long been recognized that this situation offers a unique opportunity to identify aspects of the developmental timing, natural history, and molecular genetics of pediatric leukemia in general. We reviewed both the older literature and more recent molecular biologic studies that have uncovered the basis of concordance of leukemia. Molecular markers of clonality, including unique, genomic fusion gene sequences, have provided unequivocal evidence that twin pairs of leukemia have a common clonal origin. The only plausible basis for this, first suggested more than 40 years ago, is that following initiation of leukemia in one twin fetus, clonal progeny spread to the co-twin via vascular anastomoses within a single, monochorionic placenta. This explanation has been endorsed by the identification of clonotypic gene fusion sequences in archived neonatal blood spots of individuals who subsequently developed leukemia. These analyses of twin leukemias have thrown considerable light on the natural history of disease. They reveal a frequent prenatal origin and an early or initiating role for chromosome translocations. Further, they provide evidence for a variable and often protracted latency and the need, in childhood acute lymphoblastic leukemia (ALL)/acute myeloblastic leukemia (AML), for further postnatal exposures and/or genetic events to produce clinical disease. We argue that these insights provide a very useful framework for attempts to understand etiologic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2002-12-3817DOI Listing
October 2003

Chromosome translocations and covert leukemic clones are generated during normal fetal development.

Proc Natl Acad Sci U S A 2002 Jun 4;99(12):8242-7. Epub 2002 Jun 4.

Leukaemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK.

Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.112218799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC123052PMC
June 2002