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Letizia Foroni

Publications and source records attributed to Letizia Foroni.

12 recordsLinked to original sources
PubMed2006

Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.

Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

Adult↗
PubMed2005

Analysis of balanced rearrangements of chromosome 6 in acute leukemia: clustered breakpoints in q22-q23 and possible involvement of c-MYB in a new recurrent translocation, t(6;7)(q23;q32 through 36).

BACKGROUND AND OBJECTIVES: Many clinically important oncogenes and tumor suppressor genes have been identified through analysis of recurrent chromosomal rearrangements in acute leukemia. The contribution of sporadic rearrangements to malignancy is less clear and few have been mapped in detail. In this study we investigated the significance of novel translocations and inversions of 6q in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). DESIGN AND METHODS: Breakpoints of balanced 6q rearrangements were mapped in sequential fluorescent in situ hybridization (FISH) experiments with BAC and PAC clones in 11 patients. RESULTS: Six of seven breakpoints in ALL and two in a single case of AML were localized to within a 10.5 Mb hotspot at 6q22-q23 with five analyzed to the level of a single probe. In two cases of childhood T-ALL, both carrying a t(6;7)(q23;q32 through 36), split FISH signals were produced by adjacent PAC, mapping the breakpoints to within an approximately 150 Kb region containing the genes c-MYB and AHI1. Five similar rearrangements, four also in pediatric T ALL were identified in the literature. Other 6q22-q23 translocations mapped in detail interrupted regions containing no recognized genes. 6q breakpoints outside the q22-q23 region were widely dispersed and in two were mapped to positions overlapping the cloned fragile sites FRA6E and FRA6F. The involvement of MLL was demonstrated in one case with t(6;11)(q15;q23). INTERPRETATION AND CONCLUSIONS: We identified a new primary recurrent translocation t(6;7) (q22;q23 through q26) in pediatric T-ALL. Other translocations interrupting the 6q22-q23 breakpoint cluster region did not appear to be recurrent and may contribute to leukemogenesis through a novel mechanism. Key words; chromosome 6, translocation, c-Myb, AHI1.

Acute Disease↗
PubMed2004

A fluorescence in situ hybridization map of 6q deletions in acute lymphocytic leukemia: identification and analysis of a candidate tumor suppressor gene.

With the objective of identifying candidate tumor suppressor genes, we used fluorescence in situ hybridization to map leukemia-related deletions of the long arm of chromosome 6 (6q). Twenty of 24 deletions overlapped to define a 4.8-Mb region of minimal deletion between markers D6S1510 and D6S1692 within chromosome 6 band q16. Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC). Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL). Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient. The substitution was absent among 232 normal alleles tested, leaving open the possibility that heterozygous carriers of such mutations may be susceptible to ALL. Although low in all normal hematopoietic tissues, quantitative reverse transcription-PCR showed higher baseline GRIK2 expression in thymus and T cells than other lineages. Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P = 0.0001). By contrast, elevated GRIK2 expression was measured in the myelomonocytic line THP-1 and in one patient with common ALL. Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types.

Adolescent↗
PubMed2003

Cytotoxic drugs enhance the ex vivo sensitivity of malignant cells from a subset of acute myeloid leukaemia patients to apoptosis induction by tumour necrosis factor receptor-related apoptosis-inducing ligand.

We have studied the actions of tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) on cells isolated from patients with acute myeloid leukaemia (AML). Apoptosis induction was initially assessed by quantitative morphological analysis. Only 2/19 isolates showed a > 10% increase in apoptotic cells following TRAIL treatment. However, incubation with TRAIL combined with fludarabine, cytosine arabinoside or daunorubicin resulted in additive or super-additive apoptosis induction in approximately half of the isolates. Molecular evidence of super-additive apoptosis induction by TRAIL and cytotoxic agents was obtained by quantification of caspase 3 activation, detected by Western blot analysis of poly (ADP ribose) polymerase cleavage. The ability of TRAIL and daunorubicin to induce super-additive apoptosis correlated with the ability of these agents to activate caspase 8 and to augment cellular levels of the truncated pro-apoptotic form of the BCL-2 family member BID. Our data suggest that co-administration of TRAIL with conventional cytotoxic drugs may be of therapeutic value in some patients with AML.

Acute Disease↗
PubMed2003

V(H) gene usage differs in germline and mutated B-cell chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: Given the prognostic relevance that the identification of mutated and germline subgroups of chronic lymphocytic leukemia (CLL) has recently acquired we set out to analyze in depth individual VH gene usage rearrangements in patients with mutated and germline CLL. DESIGN AND METHODS: Using sequence analysis of FR1/JH polymerase chain reaction products, the VH immunoglobulin gene configuration was analyzed in 159 rearranged IgH alleles from 154 CLL patients. Having previously identified a spatial relationship between VH gene usage and JH proximity in patients with acute lymphocytic leukemia (ALL), we performed linear and Poisson regression analysis on patients with germline and mutated CLL against VH rearrangements from normal peripheral blood. RESULTS: Sequence analysis showed that 102 patients (64%) had mutated sequences (>2% DNA base pair changes) while 57 (36%) had germline sequences. The germline CLL group showed JH proximal overusage similar to that reported in ALL patients, while the mutated CLL group showed a pattern comparable to that of the control group (peripheral blood rearranged VH sequences). The CDR3 region was statistically longer in the patients with germline CLL than in those with mutated CLL. INTERPRETATION AND CONCLUSIONS: This study highlights differences in the VDJ profile in mutated and germline CLL, consistent with the suggestion that CLL comprises two subgroups. The interpretation of these differences is that the B-cell of CLL, particularly in the germline group, may derive from a pool that has been unable to follow or complete the normal pathway of B-cell differentiation.

Alleles↗
PubMed2002

Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia.

PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL. PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count. RESULTS: Fisher's exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P <.05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P =.005). CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.

Adult↗
PubMed2002

Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia.

Minimal residual disease (MRD) was investigated in 52 children with acute lymphoblastic leukaemia (ALL), using antigen receptor gene rearrangements and reverse transcription polymerase chain reaction for fusion transcripts as molecular targets. Patients [treated according to the Medical Research Council United Kingdom ALL (MRC UKALL) XI protocol or Total XI and XIII protocols] were monitored for a median period of 45 months (range, 9-110 months). Among 17 patients who relapsed, MRD persisted for longer (66.7%, 47.1%, 53.8% and 41.7% at 0-2, 3-5, 6-9, 10-24 months respectively) than patients who remained in continuous clinical and immunological remission (n = 35) (27.3%, 11.1%, 4.3%, 8.0%). Association between MRD tests and outcome was assessed and found to be significant at all time-points. The difference in survival for MRD-positive and MRD-negative patients (using the log-rank test) was statistically significant at all time intervals, as was risk of relapse for MRD-positive patients (1.89, 2.20, 2.65 and 2.16) and MRD-negative patients (0.72, 0.82, 0.65 and 0.70). Sixteen of the 52 patients had an oligoclonal pattern at presentation but oligoclonality did not have an impact on outcome. Cox regression analysis revealed that MRD assessment is an independent and prognostically significant factor during treatment and should be used for patients' stratification in future studies.

Adolescent↗
PubMed2002

Cytogenetics and molecular genetics of acute lymphoblastic leukemia.

An important factor in the diagnosis of acute lymphoblastic leukemia (ALL) is that karyotype is an independent prognostic indicator, with an impact on the choice of treatment. Outcome is related to the number of chromosomes. For example, high hyperdiploidy (51-65 chromosomes) is associated with a good prognosis, whereas patients with near haploidy (23-29 chromosomes) have a poor outcome. The discovery of recurring chromosomal abnormalities in the leukemic blasts of patients with ALL has identified a large number of genes involved in leukemogenesis. Certain specific genetic changes are related to prognosis. The ETV6/AML1 fusion arising from the translocation (t12;21) (p13;q22) has been associated with a good outcome; the BCR/ABL fusion of (t9;22)(q34;q11), rearrangements of the MLL gene, and abnormalities of the short arm of chromosomes 9 involving the tumor suppressor genes p16INK4A have a poor prognosis. Unfortunately, the classification of patients into prognostic groups based on cytogenetics is not always as predicted. Even when other clinically based risk factors are taken into account, some patients with good-risk cytogenetic features will relapse. In the search for new measures of prognosis, it has recently emerged that the level of minimal residual disease following induction therapy can be a reliable predictor of outcome in ALL.

Chromosome Aberrations↗
PubMed2002

Molecular analysis of minimal residual disease in adult acute lymphoblastic leukaemia.

Despite intensive chemotherapy and stem cell transplantation (SCT) programmes, overall survival in adult acute lymphoblastic leukaemia (ALL) remains poor compared to that in childhood ALL. Despite clinical and morphological remission being achieved by over 80% of patients, 5-year survival is limited to 40% of patients, clearly indicating that morphology is insufficient in predicting future outcome. Molecular assessment of residual disease in bone marrow using immunoglobulin genes as markers of clonality has recently been evaluated in a large adult ALL study in our institution. Analysis of disease-free survival (DFS) rates for minimal residual disease-(MRD-) positive and -negative patients established that MRD positivity was associated with increased relapse rates at all times, being most significant at 3-5 months post-induction and beyond. Pre-autologous SCT tests are predictive of outcome, but for allogeneic SCT outcome is related to results of the tests after the procedure rather than before. The association of MRD test results and DFS was independent of, and greater than, other standard predictors of outcome and is therefore important in determining treatment for individual patients.

Adult↗
PubMed2002

Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia: a molecular based approach using T-cell receptor G and D gene rearrangements.

BACKGROUND AND OBJECTIVES: Minimal residual disease (MRD) is important in the measurement of response to treatment in childhood B- and T-cell acute lymphoblastic leukemia (ALL) and in adult B-cell ALL. Little is known about MRD evaluation in adult T-cell ALL. This study aimed to determine the prognostic significance of MRD measurements in adult T-cell ALL. DESIGN AND METHODS: T-cell receptor (TCR) gamma (G) and TCR delta (D) gene analyses were carried out at presentation in 49 patients with de novo T-ALL using a polymerase chain reaction (PCR) approach. In 26 of the patients bone marrow (BM) samples were collected at sequential time points (0-2, 3-5, 6-9, 10-24 months) after diagnosis for MRD investigation. The relationship between MRD status and clinical outcome was investigated and correlated with age, gender and white blood cell count at presentation. RESULTS: TCRG clonal gene rearrangements were found in 40 patients (82%). Eleven patients showed TCRD rearrangements (22%), in one of them as the sole molecular marker. V(gamma)I family rearrangements predominated (45 of 65 alleles) together with V(delta)1-J(delta)1/2 (9 of 13 alleles). Continuous clinical remission (CCR) occurred in 17 patients while nine patients relapsed. MRD analysis showed that negative tests during the first 6 months post-induction, and persisting negative MRD after induction were the best predictors of CCR. A positive test after 5 months was better at predicting relapse. In only four of seven patients was relapse preceded by a positive test the 5 months preceding relapse. INTERPRETATION AND CONCLUSIONS: Overall the ability of positive and negative tests to predict relapse or CCR was weaker in this cohort of adult T-ALL patients than in T- and B-lineage childhood ALL and B-lineage adult ALL. TCRG and TCRD gene analysis provides a clonal marker in the majority of adult T-ALL. These results suggest that caution should be taken in using MRD data based on TCR gene rearrangements to predict prognosis in adult T-ALL. Biological reasons may underlie differences between the performance of MRD tests in B- and T-lineage ALL. Further studies in a larger cohort of patients are needed to determine the exact role that MRD determination has in the management of T-ALL in adults.

Adolescent↗
PubMed2002

Core binding factor genes and human leukemia.

BACKGROUND: The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFb, is essential for normal hematopoiesis. Recent studies have shown that mutations and gene rearrangements involving this complex are frequently implicated in leukemogenesis. Understanding the molecular events leading to the disruption of CBF has provided important insights into our understanding of the normal regulatory pathways that control hematopoiesis and has begun to reveal how alterations in these pathways induce leukemia. INFORMATION SOURCES: Both authors are involved in the identification and characterization of chromosomal abnormalities associated with hematologic malignancy. This has led to contributions to multicenter clinical and laboratory investigations as well as publications in peer-reviewed journals. All of the references cited in this review are published in journals covered by Medline. State of the Art. The core binding factor (CBF) is a heterodimeric transcription factor composed of the RUNX1 and CBFb subunits. RUNX1 is the DNA binding element of the complex and its affinity is greatly increased in the presence of CBFb. Knock-out studies in mice have demonstrated that both RUNX1 and CBFb are necessary for definitive hematopoiesis. Furthermore, reciprocal chromosomal translocations involving both partners have been directly implicated in leukemogenesis. Evidence is now emerging that at least some of the resulting fusion proteins, namely ETV6-RUNX1, RUNX1-MTG8 and CBFb-MYH11 dominantly inhibit the function of native CBF by recruiting transcriptional co-repressor complexes. However, knock-in studies have shown that whilst expression of these fusion genes may disrupt normal hematopoiesis, this, by itself, is not sufficient for the subsequent development of leukemia. Mutations of RUNX1 have been identified in familial platelet disorder (FDP), in which there is a congenital predisposition to the development of AML and heterozygous point mutations have been identified in the RUNX1 gene in some leukemias. Moreover, a small number of cases have been reported in which amplification of RUNX1 has been detected in childhood ALL suggesting mechanisms other than loss of function, such as gene dosage may also play a role. CONCLUSIONS: Understanding the role CBF plays in normal hematopoiesis and hematologic malignancies has provided critical reagents for the accurate identification of the broad group of leukemias harboring alterations of CBF. The application of these molecular approaches has already shown an impact on the clinical management of these patients and as more information becomes available, the ability to tailor therapy to improve each patient's chance of a cure becomes feasible.

Animals↗