Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse.
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ABSTRACT:
SUBMITTER: Braggio E
PROVIDER: S-EPMC3893815 | biostudies-literature | 2012 Jul
REPOSITORIES: biostudies-literature
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Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse.
Braggio E E Kay N E NE VanWier S S Tschumper R C RC Smoley S S Eckel-Passow J E JE Sassoon T T Barrett M M Van Dyke D L DL Byrd J C JC Jelinek D F DF Shanafelt T D TD Fonseca R R
Leukemia 20120120 7
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Project description:Little is known about the extent of intraclonal heterogeneity of CLL tumor cells. We performed longitudinal whole genome analysis in 22 CLL cases with evidence of clinical progression and/or clinical relapse post therapy. We demonstrate the striking and unanticipated presence of genetic clonal heterogeneity, with at least 27% of patients exhibiting clonal evolution and 18% showing evidence of multiple subclones. We show that CLL progression can occur with multiple genetic subclones evolving either in a linear or branching manner. The analysis reveals a shift in the relative dominance of subclones with the emergence of initially minor clones after therapy all of which were very resistant to secondary therapies. This study uncovers the clinical importance of tracking subclone diversity in CLL. All patients had genome wide genetic analysis performed by aCGH on at least two sequential tumor samples >6 months apart. For the purposes of this study, we classified samples as; time point 1 (TP1) collected >6 months before starting first-line treatment for disease progression; time point 2 (TP2) consisting of tumor samples at the time of progression requiring treatment; and time point 3 (TP3) consisting of tumor samples collected >6 months after initial treatment but prior to subsequent treatments. Overall, aCGH assay was performed in 54 samples from 22 patients (2 to 4 time points analyzed per patient). Thus, 6 patients were analyzed at TP1 and TP2, 8 patients at TP2 and TP3, 2 patients at TP1 and TP3, and the remaining 6 patients were analyzed at TP1, TP2 and TP3. Keyword : array comparative genomic hybridization
2012-06-29 | E-GEOD-30217 | biostudies-arrayexpress
Project description:Little is known about the extent of intraclonal heterogeneity of CLL tumor cells. We performed longitudinal whole genome analysis in 22 CLL cases with evidence of clinical progression and/or clinical relapse post therapy. We demonstrate the striking and unanticipated presence of genetic clonal heterogeneity, with at least 27% of patients exhibiting clonal evolution and 18% showing evidence of multiple subclones. We show that CLL progression can occur with multiple genetic subclones evolving either in a linear or branching manner. The analysis reveals a shift in the relative dominance of subclones with the emergence of initially minor clones after therapy all of which were very resistant to secondary therapies. This study uncovers the clinical importance of tracking subclone diversity in CLL.
2012-06-30 | GSE30217 | GEO
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Project description:Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
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Project description:Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.
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Project description:Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10). A total of 41 driver mutations were identified, of which 11 were primary tumor-specific, 17 relapse-specific, and 13 shared (detected both in primary and relapsed tumor samples). We demonstrated that 12 of 13 shared mutations were in epigenetic modifier and spliceosome genes. Longitudinal genomic characterization revealed that in eight of 10 patients the founder leukemic clone persisted after chemotherapy and established the basis of relapse years later. Understanding the mechanisms of such quiescence in leukemic cells may help designing future strategies aimed at increasing remission duration in patients with AML.
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Project description:BackgroundIbrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment.MethodsHere, we addressed this question at the single cell level of both transcriptome and immune-phenotype. The PBMCs from a CLL patient were monitored during ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology.ResultsThis unveiled that the short clinical relapse of this patient driven by BTK mutation is associated with intraclonal heterogeneity in B leukemic cells and up-regulation of common signaling pathways induced by ibrutinib in both B leukemic cells and immune cells. This approach also pinpointed a subset of leukemic cells present before treatment and highly enriched during progression under ibrutinib. These latter exhibit an original gene signature including up-regulated BCR, MYC-activated, and other targetable pathways. Meanwhile, although ibrutinib differentially affected the exhaustion of T lymphocytes, this treatment enhanced the T cell cytotoxicity even during disease progression.ConclusionsThese results could open new alternative of therapeutic strategies for ibrutinib-refractory CLL patients, based on immunotherapy or targeting B leukemic cells themselves.
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Project description:PurposeThe identification of gene mutations and structural genomic aberrations that are critically involved in chronic lymphocytic leukemia (CLL) pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort.Experimental designWe sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations (aCNA) and LOH using single-nucleotide polymorphism (SNP) 6.0 array profiling and the mutational state of TP53, NOTCH1, and SF3B1 using Sanger sequencing. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemoimmunotherapy, during the sampling interval.ResultsWe identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients who did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations before therapy. Furthermore, we provide evidence that therapy of CLL with preexisting TP53 mutations results in outgrowth of genomically very complex clones, which dominate at relapse.ConclusionsUsing complementary technologies directed at the detection of genomic events that are present in substantial proportions of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations.
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