Clonal Architecture of Secondary Acute Myeloid Leukemia

Walter, Matthew J.; Shen, Dong; Li, Ding; Shao, Jin; Koboldt, Daniel C.; Chen, Ken; Larson, David E.; McLellan, Michael D.; Dooling, David J.; Abbott, Rachel M.; Fulton, Robert S.; Magrini, Vincent; Schmidt, Heather; Kalicki-Veizer, Joelle; O’Laughlin, Michelle; Fan, Xian; Grillot, Marcus; Witowski, Sarah; Heath, Sharon E.; Frater, John L.; Eades, William; Tomasson, Michael H.; Westervelt, Peter; DiPersio, John F.; Link, Daniel C.; Mardis, Elaine R.; Ley, Timothy J.; Wilson, Richard K.; Graubert, Timothy A.

doi:10.1056/nejmoa1106968

Cited by 698 publications

(649 citation statements)

References 35 publications

(34 reference statements)

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“…In contrast, we found CLEC12A to be aberrantly expressed on the CD34 + CD38 − cell subset in 71% (22/31) of MDS cases. In myeloid neoplasms, the presence of several malignant subclones and evidence of clonal evolution during the course of disease have been studied by several groups (Fialkow et al , 1991; Walter et al , 2012). Thus, we found it appealing to investigate the aberrant CD34 + CD38 − CLEC12A + subset as a fraction of the immature CD34 + CD38 − cells.…”

Section: Resultsmentioning

confidence: 99%

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

et al. 2016

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SummaryEvidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C‐type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML. The role of CLEC12A in MDS, however, remains to be elucidated. In this study, we found CLEC12A aberrantly expressed on the CD34+ CD38− cell compartment in 71% (22/31) of MDS patients, distributed across all Revised International Prognostic Scoring System risk groups. We showed that the CD34+ CD38− CLEC12A+ cells were indeed malignant and possessed functional stem cell properties in the long‐term colony‐initiating cell assay. As opposed to reported findings in AML, we showed that cancer stem cells from MDS samples derived from both CLEC12A positive and negative CD34+ CD38− subpopulations. Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS.

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Section: Resultsmentioning

confidence: 99%

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

et al. 2016

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“…The observed allele fractions of mutations were used to infer co-occurring mutations as has been previously described. 37 …”

Section: Discussionmentioning

confidence: 99%

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

et al. 2014

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Merkel cell carcinoma is a highly aggressive cutaneous neuroendocrine tumor that has been associated with Merkel cell polyomavirus in up to 80% of cases. Merkel cell polyomavirus is believed to influence pathogenesis, at least in part, through expression of the large T antigen, which includes a retinoblastoma protein-binding domain. However, there appears to be significant clinical and morphological overlap between polyomaviruspositive and polyomavirus-negative Merkel cell carcinoma cases. Although much of the recent focus of Merkel cell carcinoma pathogenesis has been on polyomavirus, the pathogenesis of polyomavirus-negative cases is still poorly understood. We hypothesized that there are underlying human somatic mutations that unify Merkel cell carcinoma pathogenesis across polyomavirus status, and to investigate we performed whole exome sequencing on five polyomavirus-positive cases and three polyomavirus-negative cases. We found that there were no significant differences in the overall number of single-nucleotide variations, copy number variations, insertion/deletions, and chromosomal rearrangements when comparing polyomavirus-positive to polyomavirus-negative cases. However, we did find that the retinoblastoma pathway genes harbored a high number of mutations in Merkel cell carcinoma. Furthermore, the retinoblastoma gene (RB1) was found to have nonsense truncating protein mutations in all three polyomavirus-negative cases; no such mutations were found in the polyomavirus-positive cases. In all eight cases, the retinoblastoma pathway dysregulation was confirmed by immunohistochemistry. Although polyomavirus-positive Merkel cell carcinoma is believed to undergo retinoblastoma dysregulation through viral large T antigen expression, our findings demonstrate that somatic mutations in polyomavirus-negative Merkel cell carcinoma lead to retinoblastoma dysregulation through an alternative pathway. This novel finding suggests that the retinoblastoma pathway dysregulation leads to an overlapping Merkel cell carcinoma phenotype and that oncogenesis occurs through either a polyomavirusdependent (viral large T antigen expression) or polyomavirus-independent (host somatic mutation) mechanism. Modern Pathology (2014) 27, 1073-1087; doi:10.1038/modpathol.2013.235; published online 10 January 2014Keywords: Merkel cell carcinoma; retinoblastoma; whole exome sequencing; polyomavirus Merkel cell carcinoma is a rare neuroendocrine tumor of the skin with an aggressive clinical course and an increased prevalence in the elderly and immunosuppressed. 1 The incidence of Merkel cell carcinoma has increased in the last several decades, and the United States has an estimated incidence rate of 0.32 per 100 000 persons per year. 2 Merkel cell carcinoma has a predilection for sun exposed areas, most often occurring in the head and neck region. 3 There is an overall 5-year survival rate of 40%, with stage being a significant prognosticator. 3,4 Merkel cell polyomavirus was discovered in Merkel cell carcinoma and found to be clonally integ...

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“…Recent genome sequencing shows that MDS-to-sAML transformation is characterized by multiple cycles of mutation and clonal selection [11]. However, the causal relationships between these dynamic processes and MDS transformation to sAML is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Some authors argue that one genetic event is sufficient for causing sAML [6][7][8] whereas others believe that several genetic events are required for the transformation [9,10]. The latest report on deep sequencing of the genome in patients with MDS before and after transformation to sAML [11] demonstrates complex clonal evolution with acquisition of multiple additional mutations, co-existing with the MDS founding clone. This phenomenon may represent general genetic instability without necessary causative relation.…”

Section: Introductionmentioning

confidence: 99%

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

et al. 2012

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One‐third of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML), with its concomitant poor prognosis. Recently, multiple mutations have been identified in association with MDS‐to‐sAMLtransition, but it is still unclear whether all these mutations are necessary for transformation. If multiple independent mutations are required for the transformation, sAML risk should increase with time from MDS diagnosis. In contrast, if a single critical biological event determines sAML transformation; its risk should be constant in time elapsing from MDS diagnosis. To elucidate this question, we studied a database of 1079 patients with MDS. We classified patients according to the International Prognostic Scoring System (IPSS), using either the French‐American‐British (FAB) or the World Health Organization (WHO) criteria, and statistically analyzed the resulting transformation risk curves of each group. The risk of transformation after MDS diagnosis remained constant in time within three out of four risk groups, and in all four risk groups, when patients were classified according to FAB or to the WHO‐determined criteria, respectively. Further subdivision by blast percentage or cytogenetics had no influence on this result. Our analysis suggests that a single random biological event leads to transformation to sAML, thus calling for the exclusion of time since MDS diagnosis from the clinical decision‐making process. Am. J. Hematol. © 2012 Wiley Periodicals, Inc.

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Clonal Architecture of Secondary Acute Myeloid Leukemia

Cited by 698 publications

References 35 publications

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

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