High incidence of Hox11L2 expression in children with T-ALL

Mauvieux, Laurent; Leymarie, Vincent; Hélias, Catherine; Perrusson, N; Falkenrodt, A.; Lioure, Bruno; Lutz, Patrick; Lessard, Michel

doi:10.1038/sj.leu.2402709

Cited by 42 publications

(32 citation statements)

References 27 publications

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“…Our data support the hypothesis that HOX11 deregulation is associated with a uniform cortical thymocyte stage of maturation arrest. 9,18 Such a maturation arrest is observed in pediatric as well as adult patients and is independent of the patients' age. In contrast, our study results confirm an age dependency of HOX11 expression and show a higher incidence of HOX11 expression in adults than in children.…”

Section: Hox11l2-positive Thymic T-all With Reduced Outcomementioning

confidence: 96%

“…In adolescents it has been found in around 16% and is further declining to 11% in T-ALL patients older than 20 years. [8][9][10]18,19 Reports on the FRALLE protocol with 6 HOX11L2-positive of 28 patients and the Total Therapy studies XI-XIII with 6 HOX11L2-positive of 59 patients revealed a negative prognostic impact of HOX11L2 expression. 6,7 Confirmed were these reports by an …”

Section: Discussionmentioning

confidence: 99%

“…In contrast, our study results confirm an age dependency of HOX11 expression and show a higher incidence of HOX11 expression in adults than in children. 9,18 The underlying mechanisms of HOX11 expression other than translocations are not yet understood. Recent evidence suggests that molecular cytogenetics is able to identify translocations in the vast majority of patients with aberrant HOX11 as well as HOX11L2 expression.…”

Section: Hox11l2-positive Thymic T-all With Reduced Outcomementioning

confidence: 99%

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Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

et al. 2008

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Adult T-cell acute lymphoblastic leukemia (T-ALL) continues to represent an unfavorable disease. Molecularly based treatment stratifications could help improve outcome. The prognostic impact of HOX11 and HOX11L2 expression has been an area of controversy. We have investigated 286 adult T-ALL patients enrolled into the German Multicenter ALL (GMALL) therapy protocols by comparative real-time RT-PCR. High HOX11 expression and HOX11L2 expression were predominantly seen in thymic T-ALL (P ¼ 0.031). In a multivariate analysis HOX11L2 expression proved to be an independent adverse risk factor for relapse-free survival (RFS) with a hazard ratio (HR) of 2.02 (P ¼ 0.023) and an HR for overall survival (OS) of 1.81 (P ¼ 0.021), both adjusted for the immunophenotype. HOX11 expression was found to have a favorable impact on RFS (HR 0.51; P ¼ 0.048) but did not exhibit a significant impact on OS. A subgroup analysis for thymic T-ALL revealed a more pronounced negative correlation of HOX11L2 expression with RFS (HR 3.26; P ¼ 0.002) and OS (HR 2.38; P ¼ 0.009). Although the prognostic impact of HOX11 in T-ALL is less clear, HOX11L2 expression identifies a small subset of high-risk patients, who are so far classified as standard-risk group. Thus, patients with aberrant HOX11L2 expression should be considered early as candidates for intensified treatment regimes.

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Section: Hox11l2-positive Thymic T-all With Reduced Outcomementioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Hox11l2-positive Thymic T-all With Reduced Outcomementioning

confidence: 99%

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Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

et al. 2008

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“…While the t(10;14) translocation is seen in only 4-7% of reported T-ALL cases, a recent study revealed elevated HOX11 expression levels in leukemic blasts in B50% (37/76) of pediatric T-ALL cases (Kees et al, 2003). Moreover, an additional 30% of pediatric T-ALLs exhibited inappropriate activation of the related HOX11 gene, HOX11L2 (Mauvieux et al, 2002). Clinically, patients with HOX11-positive lymphoblasts have a better prognosis when treated with modern combination chemotherapy than patients with T-ALLs involving activation of HOX11L2 (Ferrando et al, 2002(Ferrando et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

et al. 2006

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Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHl-HOX11 Tg )-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHl-HOX11 Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesisblock micronucleus assays. Additionally, IgHl-HOX11 Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHl-HOX11 Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHl-HOX11 Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

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“…Ectopic HOX11L2 expression can also be found in T-ALL without a 5q35 translocation by RT-PCR analysis. 19,130 HOX11L2 is a member of the homeobox-containing protein family. 131 Overexpression of HOX11L2 has been shown to correlate with a poor prognosis.…”

Section: Translocations Involving the Ranbp17 And Tlx3 (Hox11l2) Regimentioning

confidence: 99%

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Burg

Poulsen²,

Hunger

et al. 2004

Leukemia

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Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusionsignal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity. Leukemia ( Chromosome aberrations play an important role in hematological malignancies. 1 In ALL, most of these aberrations concern balanced translocations involving genes that play key roles in the development and function of lymphoid cells, such as transcription factors, cell cycle regulators, and signal transduction molecules. Balanced translocations can result in fusion of two genes that encode leukemia-specific chimeric (fusion) proteins. The fusion proteins have functional features that differ from the corresponding wild-type proteins and mostly play a role in leukemogenesis. In addition to the new features of the fusion protein, loss of wild-type activity due to the translocation (in some translocations enhanced by deletion of the second allele) might contribute to oncogenesis. Alternatively, chromosome translocations can result in deregulated expression of (onco)genes as a direct consequence of a translocation to a regulatory element, for example, an immunoglobulin (Ig) or T-cell receptor (TCR) enhancer. 2,3 The most frequent translocations in precursor-B-ALL are t(1;19)(q23;p13) t(4;11)(q21;q23), t(12;21)(p13;q22), and t(9;22)(q34;q11), all four of which result in generation of fusion genes. The t(1;19)(q23;p13) fuses the transcription factorencoding gene TCF3 (E2A) with the transcription factor PBX1. In t(4;11)(q21;q23), the MLL gene at 11q23, which encodes a putative DNA-binding protein, is translocated to the MLLT2 (AF4) gene. The MLL gene is involved in many other translocations in ALL and acute myeloid leukemia (AML). Until now, more than 30 partner genes have been identified. 4 The t(12;21)(p13;q22) involves th...

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High incidence of Hox11L2 expression in children with T-ALL

Cited by 42 publications

References 27 publications

Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

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