<i>RAS</i> Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Ricci, Caterina; Fermo, Elisa; Corti, Stefania; Molteni, Mauro; Faricciotti, Alessio; Cortelezzi, Agostino; Deliliers, Giorgio Lambertenghi; Beran, Miloslav; Onida, Francesco

doi:10.1158/1078-0432.ccr-09-2112

Cited by 126 publications

(116 citation statements)

References 45 publications

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“…These hyperproliferative features may reflect specific underlying genetic aberrations: in one recent series, the ASXL1 mutation in chronic myelomonocytic leukemia was associated with both a high WBC and more rapid progression to acute myeloid leukemia, 40 and RAS mutations in chronic myelomonocytic leukemia have also been associated with higher WBC and poorer survival. 41 The results of our study suggest that the presence of an NPM1 mutation in chronic myelomonocytic leukemia also appears to be a harbinger of rapid progression to acute myeloid leukemia. We performed cytogenetic risk grouping of the chronic myelomonocytic leukemia cases based on the new CCSS for primary myelodysplastic syndrome (in which 5.3% of the test set patients had a diagnosis of chronic myelomonocytic leukemia).…”

Section: Discussionmentioning

confidence: 50%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

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Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (Po0.01) and less likely to receive aggressive treatment (P ¼ 0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P ¼ 0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

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Section: Discussionmentioning

confidence: 50%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

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“…6 RAS mutations have been reported to occur as an acquired genetic event in the course of chronic myelomonocytic leukemia. 22 In these cases, the presence of the mutation has been associated with the transition from a myelodysplastic type of chronic myelomonocytic leukemia to a myeloproliferative variant of the disease. 22 A similar effect has been reported for the occurrence of an acquired JAK2 mutation in patients with chronic myelomonocytic leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…22 In these cases, the presence of the mutation has been associated with the transition from a myelodysplastic type of chronic myelomonocytic leukemia to a myeloproliferative variant of the disease. 22 A similar effect has been reported for the occurrence of an acquired JAK2 mutation in patients with chronic myelomonocytic leukemia. 23 However, in contrast to chronic myelomonocytic leukemia, no evidence of RAS or FLT3 mutations were found in cases of myelodysplastic syndromes with secondary 'monocytic evolution'.…”

Section: Discussionmentioning

confidence: 99%

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

et al. 2013

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Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (41 Â 10 9 /l) during the course of disease (5 men and 5 women; median age/range: 68 years/52-82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1-180) and persisted for a median period of 23 months (range: 2-57). Five patients died after developing monocytosis (range: 20-188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morphological shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt 'secondary' chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival.

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“…35 However, some data suggest that mutations in the RAS pathway in CMML are secondary abnormalities more important in disease progression than the initial pathogenesis. 36 Although abnormalities of CBL have been reported in 5%-18% of cases of CMML, 30,37 mutated NF1 or PTPN11 that occur in 40%-50% of cases of JMML are rare in CMML. 38 In contrast, mutations affecting the transcription factors RUNX1, CEBPA, NPM1, or WT1 have been reported in up to 30% of cases of CMML, but to date not in JMML.…”

Section: Mds/mpnmentioning

confidence: 99%

World Health Organization Classification, Evaluation, and Genetics of the Myeloproliferative Neoplasm Variants

Vardiman

Hyjek

2011

Hematology

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There is no single category in the fourth edition (2008) of the World Health Organization (WHO) classification of myeloid neoplasms that encompasses all of the diseases referred to by some authors as the myeloproliferative neoplasm (MPN) "variants." Instead, they are considered as distinct entities and are distributed among various subgroups of myeloid neoplasms in the classification scheme. These relatively uncommon neoplasms do not meet the criteria for any so-called "classical" MPN (chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, or essential thrombocythemia) and, although some exhibit myelodysplasia, none meets the criteria for any myelodysplastic syndrome (MDS). They are a diverse group of neoplasms ranging from fairly well-characterized disorders such as chronic myelomonocytic leukemia to rare and thus poorly characterized disorders such as chronic neutrophilic leukemia. Recently, however, there has been a surge of information regarding the genetic infrastructure of neoplastic cells in the MPN variants, allowing some to be molecularly defined. Nevertheless, in most cases, correlation of clinical, genetic, and morphologic findings is required for diagnosis and classification. The fourth edition of the WHO classification provides a framework to incorporate those neoplasms in which a genetic abnormality is a major defining criterion of the disease, such as those associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1, as well as for those in which no specific genetic defect has yet been discovered and which remain clinically and pathologically defined. An understanding of the clinical, morphologic, and genetic features of the MPN variants will facilitate their diagnosis.

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RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Cited by 126 publications

References 45 publications

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

World Health Organization Classification, Evaluation, and Genetics of the Myeloproliferative Neoplasm Variants

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