Atypical BCR-ABL mRNA transcripts in adult Acute lymphoblastic leukemia

Burmeister, Thomas; Schwartz, Stefan; Taubald, Almut; Jost, Edgar; Lipp, Thomas; Schneller, Folker; Diedrich, Helmut; Thomssen, Henrike; Mey, Ulrich; Eucker, Jan; Rieder, Harald; Gökbuget, Nicola; Hoelzer, Dieter; Thiel, Eckhard

doi:10.3324/haematol.11737

Cited by 37 publications

(30 citation statements)

References 15 publications

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“…8 These 2 PCR methods each included an internal control reaction as a control for RNA integrity. In addition, all samples obtained before 2006 were investigated for MLL-AF4 by a nested PCR, as described elsewhere, 9 and from 2006 onward, by a single-round PCR according to the BIOMED-1 recommendations.…”

Section: Pcr For Bcr-abl Mll-af4 Mll-enl and Mll-af9mentioning

confidence: 99%

The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group

Burmeister

Meyer

Schwartz

et al. 2009

Blood

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IntroductionMolecular aberrations involving the mixed lineage leukemia (MLL) gene on 11q23 are found in 5% to 10% of acute leukemia cases. 1 In B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), these aberrations are largely restricted to the immature CD10 Ϫ immunophenotypes (pro-B and CD10 Ϫ pre-B). The translocation t(4;11)(q22;q23) with MLL-AF4 (MLL-AFF1) fusion is known to be the most prevalent MLL fusion gene in ALL, but precise and reliable data regarding the prevalence of the different MLL fusion partner genes, that is, the MLL "recombinome" in adult ALL are lacking. Knowledge of the MLL recombinome is warranted, since MLL fusions are of interest in detecting minimal residual disease in affected patients 2,3 and also because controversy exists over whether adult ALL patients with pro-B ALL immunophenotype with or without MLL aberration might have a different prognosis. [4][5][6] We report our experience within the framework of the German Multicenter Therapy Trials for Adult ALL (GMALL) between January 2001 and October 2007 at the central diagnostic laboratory of the GMALL study group.We investigated 184 patients with a CD10 Ϫ BCP immunophenotype by reverse transcription polymerase chain reactions (RT-PCRs) for different MLL fusion genes. Since the chromosomal breakpoints in the MLL gene cluster in a relatively restricted region between exons 8 and 13 (numbering according to Nilsson et al 7 ), encompassing approximately 8.2 kb, we additionally investigated all samples by a recently published long-distance inverse polymerase chain reaction (LDI-PCR) method that also allowed the identification of unknown MLL translocation partners at the DNA level. Methods Patient materialBone marrow (n ϭ 136) and peripheral blood (n ϭ 45) samples (n ϭ 3 samples unspecified) were obtained for diagnostic purposes within the framework of the GMALL therapy studies 6/99 and 7/03 between January 2001 and October 2007. A list of GMALL study participants appears in the Supplemental Materials and Methods (available on the Blood website; see the Supplemental Materials link at the top of the online article). All samples were taken at the time of primary diagnosis and had a high blast count, as revealed by flow cytometry. The genetic investigations were done retrospectively and prospectively on archived residual material. Preparation of samples, immunophenotyping, and all RT-PCR investigations were performed at the central diagnostic laboratory of the GMALL study group in Berlin. The samples were obtained within clinical studies that were approved by the institutional ethics committees of all participating institutions. The study design and our investigations were conducted in accordance with the Declaration of Helsinki. Nucleic acid isolation and reverse transcriptionTotal RNA was isolated using the TRIZOL method (Invitrogen, Carlsbad, CA) or the RNEasy kit (QIAGEN, Hilden, Germany). Genomic DNA was For personal use only. on May 12, 2018. by guest www.bloodjournal.org From isolated using the PureGene Kit (Gentra Systems, Mi...

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Section: Pcr For Bcr-abl Mll-af4 Mll-enl and Mll-af9mentioning

confidence: 99%

The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group

Burmeister

Meyer

Schwartz

et al. 2009

Blood

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“…12 Two different RT-PCR analyses were used to assess all samples for BCR-ABL mRNA as previously described. 12 Samples with a pro-B immunophenotype were additionally analyzed for MLL-AF4 by RT-PCR 13 and for other MLL fusions by multiplex RT-PCR. 14 Residual material was archived in liquid nitrogen.…”

Section: Reverse Transcriptase Polymerase Chain Reaction Analysismentioning

confidence: 99%

Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia

Burmeister¹,

Gökbuget²,

Schwartz³

et al. 2009

Haematologica

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BackgroundThe t(9;22) and t(4;11) chromosomal translocations, which generate the BCR-ABL and MLL-AF4 fusion genes, define high-risk subtypes of acute lymphoblastic leukemia in adults. However, the prognostic impact of other rarer fusion genes is less well established in adult acute lymphoblastic leukemia than in the childhood form. Design and MethodsIn the context of the German Multicenter Therapy Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) we used reverse transcriptase polymerase chain reaction to investigate 441 cases of BCR-ABL-and MLL-AF4-negative B-precursor acute lymphoblastic leukemia for the TCF3-PBX1 (E2A-PBX1) and ETV6-RUNX1 (TEL-AML1) fusion transcripts generated by the t(1;19)(q23;p13.3) and t(12;21)(p13;q22) translocations. Both are well-known molecular alterations in pediatric acute lymphoblastic leukemia in which they have favorable prognostic implications. ResultsWe identified 23 adult patients with TCF3-PBX1 and ten with ETV6-RUNX1. In contrast to previous reports we found no significant difference in overall survival between TCF3-PBX1-positive and -negative patients. At 2 years after diagnosis all the ETV6-RUNX1-positive patients were alive and in continuous complete remission, but their long-term outcome was negatively affected by late relapses. TCF3-PBX1-positive patients exhibited a characteristic CD34 -/CD33-and mostly cyIg + immunophenotype. ETV6-RUNX1 only occurred in patients under 35 years old and was associated with a significantly lower white blood count. ConclusionsIn contrast to previous suggestions, adult patients with TCF3-PBX1-positive acute lymphoblastic leukemia do not appear to have a worse outcome than their negative counterparts. ETV6-RUNX1-positive patients had a very favorable performance status during the first few years but their long-term survival was negatively affected by late relapses. Both groups of patients are characterized by distinct clinicobiological features which facilitate their diagnostic identification. 05/1993, 06/1999 and 07/2003 have been registered at www.clinicaltrials.gov: NCT00199069, NCT00199056, NCT00198991. GMALL therapy studiesKey words: homeobox gene, core binding factor, helix-loop-helix transcription factor, pre-B ALL, common ALL.Citation: Burmeister T, Gökbuget N, Schwartz S, Fischer L, Hubert D, Sindram A, Hoelzer D, and Thiel E. Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia. Haematologica. 2010; 95:241-246. doi:10.3324/haematol.2009 This is an open-access paper. Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia

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“…27,28 Analysis of MLL-AF4 was only done in CD10 Ϫ samples because the presence of MLL-AF4 is nearly exclusively restricted to this subgroup in B-precursor ALL. 29 BAALC expression levels were measured as reported previously.…”

Section: Diagnostic Analysesmentioning

confidence: 99%

Overexpression of LEF1 predicts unfavorable outcome in adult patients with B-precursor acute lymphoblastic leukemia

Kühnl

Gökbuget

Kaiser

et al. 2011

Blood

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Aberrant activation of the Wnt pathway plays a pathogenetic role in various tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). LEF1, a key mediator of Wnt signaling, has been linked to leukemic transformation, and recurrent mutations of LEF1 have been identified in pediatric T-ALL. Here we evaluated the prognostic significance of LEF1 expression in B-precursor ALL patients. LEF1 expression was determined by quantitative real-time RT-PCR in 282 adult Bprecursor ALL patients treated on 06/99 and 07/03 GMALL trials. Patients were grouped into quartiles (Q1-Q4) according to LEF1 expression levels (LEF1 high, Q4; n ‫؍‬ 71; LEF1 low, Q1-Q3; n ‫؍‬ 211). Patients with high LEF1 expression had a significantly shorter relapse-free survival (RFS) compared with low LEF1 expressers (5-year RFS: LEF1 high, 27%; LEF1 low, 47%; P ‫؍‬ .05). Importantly, high LEF1 expression was also associated with inferior RFS in standard-risk patients and was independently predictive for RFS (P ‫؍‬ . IntroductionLong-term outcome of most adult patients with B-precursor acute lymphoblastic leukemia (ALL) remains unsatisfactory, although intensified therapy regimens have resulted in high complete remission (CR) rates. 1,2 During the last decade, overall survival (OS) of adult ALL patients has primarily been improved by risk-adapted treatment stratification based on clinical and molecular risk factors and by the use of tyrosine kinase inhibitors in BCR-ABL-positive patients. In the large, heterogeneous group of standard-risk patients without established risk factors, the relapse rate is still approximately 40% to 50% and not predictable with pretreatment markers. 3,4 Prospective evaluation of minimal residual disease (MRD) has improved individual risk assessment of standard-risk patients; however, the identification of new prognostic factors is of particular interest for this subgroup of ALL. Moreover, characterization of aberrant signaling pathways with prognostic relevance in standard-risk B-precursor ALL might elucidate molecular mechanisms of therapy resistance and may help to develop novel targeted therapies for these patients.Lymphoid enhancer factor 1 (LEF1) is a member of the LEF/T-cell factor family of transcription factors and a key mediator of the canonical Wingless-type (Wnt) pathway. 5 Wnt activation results in the accumulation of ␤-catenin, which translocates to the nucleus and forms a complex with LEF/T-cell factor DNA binding proteins, thereby enhancing the transcription of target genes. Wnt downstream target genes (eg, MYC, CCND1) are involved in the regulation of central cellular processes, such as differentiation, cell cycle, proliferation, and survival. 6 Activation of the Wnt pathway has been implicated in leukemic transformation 7-9 and was shown to promote proliferation and survival of leukemic cells in vitro. [9][10][11] In ALL patients, a frequent down-regulation of Wnt antagonists sFRP1, sFRP2, sFRP4, sFRP5, WIF1, DKK3, and HDPR1 by promoter hypermethylation has been observed. 12 T...

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Atypical BCR-ABL mRNA transcripts in adult Acute lymphoblastic leukemia

Cited by 37 publications

References 15 publications

The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group

The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group

Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia

Overexpression of LEF1 predicts unfavorable outcome in adult patients with B-precursor acute lymphoblastic leukemia

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