Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia

Abstract

Key Points• Relapsed AML with NPM1 mutation is genetically related to the primary leukemia and characterized by an increase in high-risk aberrations.• DNMT3A mutations show the highest stability and thus may precede NPM1 mutations.Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1 mut ) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n 5 10; UPDs, n 5 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n 5 46; UPDs, n 5 10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes (

Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

“…A number of authors have recommended the development of strategies to target and eliminate clonal reservoirs of HSCs containing pre-leukemic mutations. 13,15,16,18 Such strategies must take into account that CH appears to be quite common in elderly asymptomatic individuals and that absolute risks for progression to hematological malignancy are low. On the basis of the observations described here, targeting known pre-leukemic driver mutations may address only a fraction of the at-risk individuals.…”

“…12 Mutations of these so-called "early genes" can persist in HSCs of patients in remission, creating reservoirs of pre-leukemic clones that can engender a relapse. [13][14][15][16] Early gene mutations are also detectable in mature blood cells of patients with AML and some subjects with skewed X-inactivation, but ostensibly normal hematopoiesis. 13,16,17 The frequencies of the mutant alleles in these cases indicate the mutant cells must have undergone clonal expansions, despite retaining a capacity to differentiate normally.…”

Leukemic stem cells: identification and clinical application

“…In 2012, we showed that immunophenotypically defined subpopulations of cells prominent at relapse could be traced back as very minor immature (CD34+/CD38−/dim) subpopulations of cells at diagnosis [32], again suggesting the importance of the CD34+/CD38− leukemic stem cell fraction. Since LSC are currently followed during therapy as biomarker of treatment efficacy and as prognostic factor for relapse, it is of great relevance to identify all (possibly minor) LSC populations that are potentially capable of causing relapse [37].…”

Longitudinal qPCR monitoring of nucleophosmin 1 mutations after allogeneic hematopoietic stem cell transplantation to predict AML relapse

“…3 More than 40 mutations have been described, but 75% of cases show the same genetic alteration in exon 12, named NPM1 mutation A. NPM1 mut represent relatively early events in leukemogenesis, and thus can be considered stable markers to be tracked throughout leukemia history and clonal evolution. 4,5 In line with that, numerous studies have demonstrated the usefulness of landmark analyses and longitudinal monitoring of NPM1 mut in AML patients after chemotherapy. 6,7 However, information on the clinical utility of NPM1 mut quantitative monitoring in the post-transplantation setting are to date more limited, [7][8][9] and thus represent the specific focus of our present study.…”

“…It should however be emphasized that NPM1 mut is present in only a subset of AML patients, and in even fewer of those who receive allogeneic HSCT. Moreover, even though generally stable over the disease course, NPM1 mut can be lost during clonal evolution, 4 as occurred also in one of the cases included in our analysis. In this view, the evaluation of earlier events in leukemogenesis, such as mutations in DNMT3A or IDH1/2, appears worthy of future investigation: although these preleukemic mutations have been shown to persist after chemotherapy even in patients who will not relapse, 14,15 in allogeneic HSCT the persistence of host hematopoiesis, especially if of clonal origin, would bring no benefit whatsoever, and might be more easily and safely targeted by 'soft' therapeutic measures such as tapering of immunosuppressants.…”