AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions

Haferlach, Claudia; Dicker, Frank; Kohlmann, Alexander; Schindela, Sonja; Weiss, Tamara; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Torsten

doi:10.1038/leu.2010.22

Cited by 64 publications

(59 citation statements)

References 8 publications

(16 reference statements)

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“…Approximately 40% of AML with inv(16) or t(16;16) patients have secondary cytogenetic abnormalities such as trisomies 8, 21, and 22, and 70% of them have mutations in KIT, FLT3 and RAS [4,5]. The presence of a KRAS mutation in our patient is in agreement with other studies where secondary genetic lesions specifically in the RAS family of genes have been described in patients with AML with inv(16) and led to the hypothesis that these alterations represent cooperative secondary events with the CBFB/MYH11 translocation [5,6]. Several components of the RNA splicing machinery including PRPF40B have been found mutated in AML [7].…”

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Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts

et al. 2016

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Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts To the Editor: Acute myeloid leukemia (AML) with inv(16)(p13.1q22) [inv(16)] or t(16;16)(p13.1;q22) [t(16;16)] is one of the biologically distinct AMLs in the category of AML with recurrent genetic abnormalities that does not account for blast percentage in the 2008 World Health Organization (WHO) classification. AML with inv(16) accounts for 5-8% of AML and it is usually associated with a relatively favorable prognosis with complete remission rates of 87% [1][2][3]. It usually presents as acute myelomonocytic leukemia and increased eosinophils by morphology in the bone marrow (BM) and/or peripheral blood (PB). One of the most distinctive features is the presence of abnormally large, coarse, purple-violet granules in the eosinophils and eosinophilic precursors. Vacuolation or hypersegmentation can be often observed in eosinophils. Monocytic and granulocytic differentiation is present although granulocytes may show dysplastic features such as cytoplasmic hypogranulation and/or abnormal segmentation.Here we describe an extremely rare case of AML with inv(16). A 54-year-old man presented with respiratory failure and hemoptysis. On admission, complete blood cell (CBC) count showed normocytic anemia, thrombocytopenia and mild monocytosis without leukocytosis or left-shift. Since three days after admission, CBC count has showed persistent leukocytosis (up to 38.3 3 10 3 /uL) with absolute monocytosis (up to 31.85 3 10 3 /uL). However, no circulating blasts or eosinophils were noted. Flow cytometric analysis on PB cells demonstrated an abnormal immunophenotype in the monocytic population with aberrant expression of CD2 and CD3 without the coexistence of myeloid blasts. The patient was started on Hydroxyurea (500 mg/daily) for the presumed diagnosis of chronic myelomonocytic leukemia. Subsequent BM biopsy showed hypercellular marrow (70-80%) with trilineage hematopoietic maturation and increased eosinophils (Fig. 1C). A 500-cell differential count on adequate aspirate smears demonstrated 0% blasts, 17% CORRESPONDENCE myelocytes to segmented neutrophils, 9% eosinophils, 5% monocytes, 42% erythroid precursors, 21% lymphocytes, and 6% plasma cells. Interestingly, many mature and immature eosinophils were present with large coarse basophilic granules, abnormal nuclear segmentation, and occasional cytoplasmic vacuoles (Fig. 1D-F). In addition, mild dysgranulopoiesis was noted. A CD34 immunohistochemical stain demonstrated the absence of blasts in the BM biopsy (inlet in Fig. 1C). PDGFRA and PDGFRB translocations were negative by fluorescent in situ hybridization (FISH). BCR/ABL1 fusion transcripts and KIT (exons 8 and 17) mutations were negative by polymerase chain reaction (PCR). Cytogenetic testing showed a 46 XY, inv (16) (Fig. 1A). FISH analysis using break-apart probes in the BM cells confirmed the presence of CBFB/MYH11 translocation in 53 of 200 (27%) interphase nuclei (Fig. 1B). A comprehensive...

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Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts

et al. 2016

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“…For instance, an NRAS mutation was identified in an AML specimen with a normal karyotype together with 11 other mutations in the coding region of several genes including IDH1 and NPM1. 46 In a study by Haferlach et al, 47 rearrangement with 22% showing at least two alterations in this pathway. These data indicate that by far more than two molecular events may be relevant for the pathogenesis of many AML cases and distinct alterations affecting the same pathway may be a common finding in this disease.…”

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confidence: 98%

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

et al. 2012

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RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signalregulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34 þ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni-and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML.

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“…Interestingly, in these cases, secondary mutations or somatic loss of the remained wild-type allele is observed, suggesting that NF1 acts as a tumor-suppressor gene according to Knudson's two-hit model [12,13]. In this context, many recent studies have investigated the incidence of NF1 deletion in AML but the frequency of this abnormality fluctuates according to screening methods used and size and heterogeneity of the cohorts analyzed [6,7,9,14].…”

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confidence: 99%

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

et al. 2013

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On behalf of the French ALFA groupGermline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small~0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. Am. J.

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AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions

Abstract: References1 Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N et al. AML with CBFB-MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions

Cited by 64 publications

References 8 publications

Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts

Acute myeloid leukemia with inv(16)(p13.1q22), abnormal eosinophils, and absence of peripheral blood and bone marrow blasts

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

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