Adult T‐biphenotypic acute leukaemia: clinical and biological features and outcome

Rubio, Marie‐Thérèse; Dhédin, Nathalie; Boucheix, Claude; Bourhis, J.; Reman, Oumédaly; Jm, Boiron; Gallo, John H.; Lhéritier, Véronique; Thomas, Xavier; Fière, D; Jp, Vernant

doi:10.1046/j.1365-2141.2003.04715.x

Cited by 32 publications

(32 citation statements)

References 29 publications

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“…Mixed myeloid/T-lymphoid leukemias have been described previously and are thought to represent a variety of diseases with a large genetic heterogeneity, ranging from myeloid leukemias with aberrant expression of only one or few T-cell markers, to "true" biphenotypic leukemias. [34][35][36][37] The T-cell gene most consistently associated with the patient group described here was CD7, which is known to be expressed by a considerable proportion of immature AMLs, [38][39][40] suggesting that the precursor cell in which transformation occurred already had undergone some initial myeloid differentiation. Interestingly, CD7 expression is frequently associated with AMLs carrying CEBPA mutations.…”

Section: Discussionmentioning

confidence: 99%

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

Wouters

Jordà²,

Keeshan

et al. 2007

Blood

173

182

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Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of Tcell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML. IntroductionAcute myeloid leukemia (AML) is a heterogeneous disease with respect to its underlying genetic abnormalities and clinical biology. 1 It has therefore been postulated that AML, although always characterized by a malignant accumulation of myeloid progenitor cells, in fact represents not a single disease, but a group of neoplasms. Cytogenetic and molecular analyses, studying specific chromosomal translocations and mutations, are used to identify subgroups of AML with distinct biologic and clinical behavior. Recent developments in microarray research have resulted in further improvements in the characterization of the molecular heterogeneity of AML, 2 and gene expression profiling (GEP) studies have demonstrated that specific chromosomal aberrations, such as the common translocations t(8;21), t(15;17), and inv(16), correlate with unique expression signatures. [3][4][5] In a GEP study of 285 cases of de novo AML, we found that specific expression profiles are associated with other recurrent genetic aberrations such as mutations in NPM1 and alterations involving MLL, and with overexpression of the proto-oncogene EVI1 as well. 4,6 Some AMLs lacking these particular abnormalities were found to express the same characteristic profiles, suggesting that deregulation of the same pathways had occurred through yet-unknown mechanisms. This study also showed that 2 distinct expression clusters (no. 4 and no. 15) consisted primarily of AML cases with mutations in CEBPA, the gene encoding the basic leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣). C/EBP␣ is a critical regulator of hematopoietic stem cell (HSC) homeostasis and myeloid differentiation, [7][8][9][10] and multiple studies have shown that C/EBP␣ function is frequently ...

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Section: Discussionmentioning

confidence: 99%

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

Wouters

Jordà²,

Keeshan

et al. 2007

Blood

173

182

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“…Samples were processed according to standard cytogenetic techniques and karyotypes were described according to the International System for Human Cytogenetic Nomenclature (25). ETV6 rearrangements were detected using differentially labeled ETV6 exon-specific cosmids 179A6 (exon 1A), 50F4 (intron 1 and exon 2), 50F4 (exon 2), 163E7 (exons 3-5), 54D5 (exons [5][6][7][8], and 148B6 (exon 8; kindly provided by P. Marynen, Center for Human Genetics, University of Leuven, Leuven, Belgium; ref. 26).…”

Section: Methodsmentioning

confidence: 99%

ETV6-NCOA2: A Novel Fusion Gene in Acute Leukemia Associated with Coexpression of T-Lymphoid and Myeloid Markers and Frequent NOTCH1 Mutations

Strehl

Nebral

König

et al. 2008

Clinical Cancer Research

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Purpose:The ETV6 gene has been reported to be fused to a multitude of partner genes in various hematologic malignancies with 12p13 aberrations. Cytogenetic analysis of six cases of childhood acute lymphoblastic leukemia revealed a novel recurrent t(8;12)(q13;p13), suggesting involvement of ETV6. Experimental Design: Fluorescence in situ hybridization was used to confirm the involvement of ETV6 in the t(8;12)(q13;p13) and reverse transcription-PCR was used to identify the ETV6 partner gene. Detailed immunologic characterization was done, and owing to their lineage promiscuity, the leukemic blast cells were analyzed for NOTCH1 mutations. Results: We have identified a novel recurrent t(8;12)(q13;p13), which results in a fusion between the transcriptional repressor ETV6 (TEL) and the transcriptional coactivator NCOA2 (TIF2) in six cases of childhood leukemia expressing both T-lymphoid and myeloid antigens. The ETV6-NCOA2 transcript encodes a chimeric protein that consists of the pointed protein interaction motif of ETV6 that is fused to the COOH terminus of NCOA2, including the cyclic AMP^responsive element binding protein^binding protein (CBP) interaction and the AD2 activation domains. The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases suggests that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. In addition, ETV6-NCOA2 leukemia shows a high frequency of heterozygous activating NOTCH1 mutations, which disrupt the heterodimerization or the PESTdomains. Conclusions: The ETV6-NCOA2 fusion may define a novel subgroup of acute leukemia with T-lymphoid and myeloid features, which is associated with a high prevalence of NOTCH1 mutations.Acute leukemia is subdivided into myeloid or lymphoid according to cytology and immunophenotyping. However, using these criteria, a minor proportion of acute leukemia is difficult to unambiguously assign because the blast populations do not allow classification in either a pure myeloid or lymphoid category (1). Such cases are designated as biphenotypic acute leukemia (BAL) or acute leukemia of ambiguous lineage.In an effort to establish objective diagnostic criteria for defining such leukemias, several different immunologic classification and scoring systems, which are mostly based on the number and specificity of the lymphoid and myeloid markers expressed by the blast cells, have been introduced (1 -4). Based on these categorizations, the prevalence of BAL has been determined to range from 2% to 5% in adult and childhood acute leukemia (5 -7). Coexpression of myeloid and B-lymphoid antigens occurs in approximately 65% to 70%, whereas Tlymphoid and myeloid antigens account for 25% of all BAL and thus for V1% of acute leukemia (6).As a basic principle, the classification of hematopoietic neoplasms should attempt to incorporate immunophenotypic, biologic, genetic, and clinical features to define specific disease

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“…Several reports suggested that patients with MPAL have poor treatment outcomes [1][2][3][4][5]. The low frequency of MPAL in pediatric patients makes it difficult to discover clinical insights of MPAL and the best therapeutic approach for these patients.…”

Section: Introductionmentioning

confidence: 99%

Children Diagnosed as Mixed-Phenotype Acute Leukemia Didn’t Benefit from the CCLG-2008 Protocol, Retrospective Analysis from Single Center

Ashwani

Zhang

et al. 2014

Indian J Hematol Blood Transfus

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Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia with a poor clinical outcome which lacks specific therapy. To evaluate the therapeutic efficiency of CCLG-2008 protocol used for acute lymphoblastic leukemia (ALL) in China on MPAL children who were initially diagnosed as ALL by morphology, we reviewed patients' database diagnosed as ALL and MPAL according to WHO classification and compared their outcomes from July 2008 to June 2012. Total newly enrolled ALL in this study were 309 cases by morphology, in which ten cases were identified as MPAL mainly by immunophenotyping: B? myeloid (3/10), T? myeloid (2/10), B ? T (4/10), trilineage (1/10). Two cases were classified as intermediate risk (IR) and 8 cases were high risk (HR) according to the CCLG-2008 criteria. Only one case of IR survived and others died due to primary resistance of chemotherapy and relapse. Compared with MPAL, ALL children in IR and HR had a longer survival (28.1 vs 9.5 months, p \ 0.0001) and lower relapse (16.3 vs 85.7 %, p = 0.0002). In a summary, our result indicated that MPAL in children is a poor-risk disease which needs personalized therapy to improve outcome.

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Adult T‐biphenotypic acute leukaemia: clinical and biological features and outcome

Cited by 32 publications

References 29 publications

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

ETV6-NCOA2: A Novel Fusion Gene in Acute Leukemia Associated with Coexpression of T-Lymphoid and Myeloid Markers and Frequent NOTCH1 Mutations

Children Diagnosed as Mixed-Phenotype Acute Leukemia Didn’t Benefit from the CCLG-2008 Protocol, Retrospective Analysis from Single Center

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