Using 4peaks license#

Median age was 51 years (range, 35-68 years) 18 were men and 9 were women. Patient demographics are shown in Table 1. Patients presented between April 1983 and September 2004. Because samples were chosen based on their availability, there was a bias toward samples with relatively high white blood cell counts.

Using 4peaks license#

Samples were stored in the tissue bank of Barts and the London School of Medicine and Dentistry (Human Tissue Authority deemed license 12199). Ethics approval was obtained from the East London and City Research Ethics Committee (ref P1/03/310). Ethical approval was obtained from the local research ethics committee, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Sufficient paired diagnostic and relapse blood and bone marrow samples for analysis were available from 27 patients with AML.

To evaluate this hypothesis, 27 paired diagnosis and relapse AML samples were studied with the use of array-based genome-wide mapping to identify regions of segmental UPD and gene-specific mutation analysis.

18 A possible mechanism for relapse in AML is one in which a heterozygous mutation is followed by a recombination event leading to homozygosity and clonal evolution. 15 Studies of acquired UPD in diagnostic AML samples give a frequency of 15% to 20%, 16, 17 with the largest study to date having analyzed 454 samples. 14 Homozygous single gene mutations are known to occur in AML, and these are associated with mitotic recombination or possibly a nondisjunction event leading to acquired uniparental disomy (UPD), also known as acquired isodisomy. 14 Some of these have been found to have an increased dosage of mutant FLT3 at disease recurrence, suggesting a clonal outgrowth of a cell with a homozygous or hemizygous mutation. 13 When FLT3 ITD is detected at diagnosis, the same mutation is noted at relapse in 75% of cases. Single gene mutations are an additional biologic risk factor for relapse, with FLT3 internal tandem duplication (ITD) being an important predictor of poor prognosis. 6 Hence, there is a compelling urgency to determine mechanisms of resistance to identify appropriate alternative treatment strategies. Although a second remission may be achieved, it is rarely sustained, even when allogeneic stem cell transplantation is successful, such that only 20% of adult patients survive at 4 years. 4, 5 Data from our institution similarly show that two-thirds who achieve first complete remission, subsequently relapse. 3 Despite this success, reemergence of leukemia is the rule rather than the exception at least 50% of younger patients and 80% of those older than 60 years will see their leukemia return within 5 years. 1-3 Complete remission, determined clinically, morphologically, immunologically, and sometimes at the molecular level, is reliably reported to be achieved in up to 80% of patients in this age group. We conclude that acquisition of segmental UPD and the resulting homozygous mutation is a common event associated with relapse of AML.ĭramatic advances have been made during the past 40 years in the treatment of acute myeloid leukemia (AML) such that 40% to 50% of patients presenting younger than 60 years can be cured with initial therapy. Finally, a single patient with AML acquired segmental UPD of chromosome 4q, for which the candidate gene is unknown. One patient acquired segmental UPD of 19q that led to homozygosity for a CEBPA mutation 207C>T. Three further AML samples had evidence of acquired segmental UPD of 13q in a subclone of the relapsed leukemia.

Six were segmental UPDs of chromosome 13q, which were shown to lead to a change from heterozygosity to homozygosity for internal tandem duplication mutation of FLT3 ( FLT3 ITD). Newly acquired segmental UPDs were observed at relapse in 11 AML samples (40%). DNA from 27 paired diagnostic and relapsed AML samples were analyzed using genotyping arrays. This study aimed to discover if clonal evolution from heterozygous to homozygous mutations by mitotic recombination provides a mechanism for relapse. At diagnosis, acquisition of segmental uniparental disomy (UPD) by mitotic recombination has been reported in 15% to 20% of AML cases, associated with homozygous mutations in the region of loss of heterozygosity. Despite advances in the curative treatment of acute myeloid leukemia (AML), recurrence will occur in the majority of cases.