Hilden, J. M. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108, 441-451

Baylor College of Medicine, Houston, Texas, United States
Blood (Impact Factor: 10.45). 08/2006; 108(2):441-51. DOI: 10.1182/blood-2005-07-3011
Source: PubMed


Infant acute lymphoblastic leukemia (ALL) has a poor therapeutic outcome despite attempts to treat it based on prognostic factor-guided therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/11q23 rearrangement. All infants enrolled on Children's Cancer Group (CCG) 1953 were tested for MLL rearrangement by Southern blot and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or "other") by reverse-transcriptase polymerase chain reaction (PCR). One hundred fifteen infants were enrolled; overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL-rearranged cases was 33.6% and for MLL-nonrearranged cases was 60.3%. The difference in EFS between the 3 major MLL rearrangements did not reach statistical significance. Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis of CD10 negativity, age younger than 6 months, and MLL rearrangement, in that order. Toxicity was the most frequent cause of death. Relapse as a first event in CCG 1953 was later (median, 295 days) compared with CCG 1883 historic control (median, 207 days). MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but molecular 11q23 translocation partners do not predict outcome.

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    • "A unique feature of the MLL locus is that it is subject to an extremely wide variety of rearrangements, including translocations with >50 partner genes on various chromosomes, as well as deletions, inversions, internal duplications and gene amplifications [4-6]. There are conflicting reports on the relative GC responses of patients with different MLL translocations [7,8], but those with t(4;11) translocations appear particularly resistant [3,8,9]. The biological basis for the documented GC resistance of patients with MLL-disease has not been explored but has generally been assumed to be due to the oncogenic effects of translocated MLL fusion proteins. "
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    ABSTRACT: Rearrangement of the mixed-lineage leukemia gene (MLL) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of MLL. In this study we have further explored the relationship between MLL status and GC sensitivity. Negative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL-rearrangements suggested that this relationship represented expression of wild-type MLL. Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis. The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.
    Full-text · Article · Oct 2010 · Molecular Cancer
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    • "However, outcomes for infants with positive mixed lineage leukemia (MLL) gene rearrangements, found in 70–80% of infant ALL cases studied with molecular techniques, remain poor, despite the use of intensive multiagent chemotherapy in combination with hematopoietic stem cell transplantation [1] [4] [5]. Multivariate analyses on recently conducted largescale clinical studies have revealed several risk factors among infants with ALL, including a rearranged MLL gene, younger age (<3 or 6 months), very high white blood cell count (≥300,000/␮L), and poor response to initial prednisone therapy [2] [3]. Among these factors, presence of MLL gene rearrangement is the most important, significantly correlated with both the adverse clinical features and the poor prognosis that is characteristic of this distinct subtype of childhood ALL [4]. "
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    ABSTRACT: The treatment outcome for infant acute lymphoblastic leukemia (ALL) with positive MLL gene rearrangements remains poor. We analyzed whether additional chromosomal abnormalities (ACA) other than 11q23 translocation could affect the disease behavior and its prognosis. Eighteen of seventy-four patients with infant acute lymphoblastic leukemia showed ACA, including three-way translocations in four, other novel translocations in four, and complex structural chromosomal changes in four. Only age less than 6 months and positive central nervous system leukemia were significant prognostic factors by multivariate analysis. However, overall survival rates were worse in patients with ACA compared to those with non-ACA. Genetic alterations induced by additional chromosomal changes may be associated with disease progression and poorer overall survival rates in infants with MLL-rearranged ALL.
    Full-text · Article · Nov 2008 · Leukemia Research
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    ABSTRACT: Tese (doutorado)—Universidade de Brasília, Faculdade de Medicina, 2009. Em crianças, as leucemias, predominantemente do tipo aguda, são a forma mais comum de câncer. Informações a respeito das alterações genéticas recorrentes são importantes para a confirmação diagnóstica, caracterização biológica e apresentam grande valor prognóstico nas leucemias. No entanto, no Distrito Federal, não há relatos a respeito de suas freqüências. Utilizando-se as técnicas de obtenção de metáfases a partir do cultivo de células de medula óssea e RT-PCR foram pesquisadas as alterações genéticas recorrentes em 133 pacientes pediátricos portadores de leucemia, no período de 2005 a 2007, correspondendo a 78,70% do total registrado no Hospital de Apoio de Brasília. Observaram-se um total de 88 casos de LLA de linhagem B, 34 de LMA, sete de leucemia aguda bifenotípica e quatro de LMC, correspondendo, respectivamente, a 66,17%, 25,56%, 5,26% e 3,01% do total analisado. Entre os 79 casos com análise cariotípica completa, 47 apresentaram cariótipo normal e 32 outros evidenciaram alterações cromossômicas, sendo: hiperdiploidia (12), hipodiploidia (7), pseudodiploidia (12) e trissomia do 21 (1). Transcritos híbridos recorrentes foram identificados em 17 casos de LLA de linhagem B, sendo BCR/ABL p190 (1), E2A/PBX1 (5), TEL/AML1 (10) e MLL/ENLA1 (1) e em onze de LMA: AML1/ETO (5), PML/RAR (3), CBF /MYH11 (3). Para os transcritos: MLL/AF4, MLL/AF9, MLL/ENLA2 e MLL/ELL, nenhuma amplificação foi observada. Para cada transcrito foi verificada variação no valor das freqüências obtidas ano a ano. Questões relacionadas à heterogeneidade étnica são discutidas, sugerindo-se influência deste fator na variação encontrada. Os valores referentes às freqüências do transcrito TEL/AML1 identificados, no presente trabalho, são inferiores à média de 25% relatada em países industrializados. Análise comparativa da freqüência do referido transcrito é realizada entre países com diferentes graus de industrialização, identificando-se possível correlação entre este fator e a freqüência de TEL/AML1, o que leva a considerar a possibilidade de ocorrência de uma etiologia infecciosa para a leucemia infantil. Não houve concordância entre os resultados obtidos a partir das análises citogenética e molecular. A análise molecular, por RT-PCR, foi considerada como técnica ideal para a detecção de transcritos híbridos, enquanto que a análise citogenética contribuiu para a identificação de alterações cromossômicas numéricas, alterações estruturais não recorrentes e pseudodiploidias sem transcrito correspondente. O trabalho realizado permitiu a instalação de uma Unidade de Diagnóstico Molecular de Leucemias no Distrito Federal, ao possibilitar a incorporação do exame molecular no grupo de exames realizados ao diagnóstico em todos os pacientes com suspeita de leucemia, registrados no Hospital de Apoio de Brasília. _______________________________________________________________________________ ABSTRACT Leukemias, mainly of the acute type, are the most common form of cancer in children. Information about recurrent genetic alterations is important for diagnostic confirmation and biological characterization, and this represents great prognostic value in leukemias. However, in the Federal District there are no reports on their frequency. Using techniques that obtain metaphases from the cultivation of bone marrow cells and RT-PCR, recurrent genetic alterations were studied in 130 pediatric leukemia patients, from 2005 to 2007, corresponding to 78,70% of the total number recorded at the Hospital de Apoio of Brasília. A total of 88 cases of LLA of B lineage, 34 of LMA, seven of acute biphenotypic leukemia and four of LMC were observed, corresponding, respectively, to 66.17%, 25.56%, 5.26% and 3.01% of the whole group analyzed. Among the 79 cases with complete karyotypic analysis, 47 presented a normal karyotype and 31 others showed chromosomal alterations, which were divided thus: hyperdiploidy (12), hypodiploidy (7), pseudodiploidy (12) and trisomy-21 (1). Recurrent hybrid transcripts were identified in 17 cases of LLA of B lineage, and these were BCR/ABL p190 (1), E2A/PBX1 (5), TEL/AML1 (10) and MLL/ENLA1 (1) and in eleven of LMA: AML1/ETO (5), PML/RAR (3), CBF /MYH11 (3). For transcripts MLL/AF4, MLL/AF9, MLL/ENLA2 and MLL/ELL, no amplification was observed. For each transcript there was a variation in the value of frequencies obtained year on year. Questions relating to ethnic heterogeneity are discussed, suggesting that this is a factor in the variation encountered. The values referring to frequencies in the TEL/AML1 transcripts identified in the current work are below the average of 25% reported in industrialized countries. Comparative analysis of the frequency of the transcript is carried out among countries with different levels of industrialization, identifying a possible correlation between this factor and the frequency of TEL/AML1, which leads one to consider the possibility of there being an infectious etiology for child leukemia. There was no match between the results obtained from cytogenetic and from molecular analyses. Molecular analysis, by RT-PCR, was considered to be the ideal technique to detect hybrid transcripts, while cytogenetic analysis helped to identify numerical chromosomal alterations, non-recurrent structural alterations and pseudodyploidies with no corresponding transcript. This work allowed a Molecular Leukemia Diagnosis Unit to be installed in the Federal District, making it possible for the molecular test to be incorporated in the group of tests carried out when diagnosing all patients with suspected leukemia, registered at the Hospital de Apoio of Brasília.
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