Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG)

Kees, Ursula R.; Heerema, Nyla A.; Kumar, Rolee; Watt, Paul M.; Baker, David L.; La, Marzano; Uckun, Fatih M.; Sather, Harland N.

doi:10.1038/sj.leu.2402892

Cited by 74 publications

(62 citation statements)

References 35 publications

(38 reference statements)

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“…In a large pediatric study a positive prognostic impact has been shown for t (10;14). 23 Two other studies have indicated a trend toward a better outcome in children with high HOX11 expression. 8,24 Ferrando et al 17 found an improved OS in 16 HOX11-positive of 52 adult patients and suggested that they might be at greater risk from treatment related mortality of allografting.…”

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

confidence: 99%

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: 99%

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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“…Aberrant activation of HOX11 can be achieved by a t(10;14)(q24;q11) chromosome rearrangement, juxtaposing the HOX11 gene downstream of the T-cell receptor (TCR) a/d regulatory elements (Dube´et al, 1986(Dube´et al, , 1991. 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).…”

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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“…HOX11 was originally isolated from the site of the recurrent t(10;14)(q24;q11) translocation in T-ALL (Dube et al, 1991;Hatano et al, 1991;Kennedy et al, 1991;Lu et al, 1991;Dear et al, 1993) and is aberrantly expressed in 3-5% of pediatric and up to 30% of adult T-ALL cases (Berger et al, 2003;Ferrando and Look, 2003;Kees et al, 2003). Similar to other HOX genes, HOX11 plays an important role in embryonic development, and functions as a master transcriptional regulator necessary for the genesis of the spleen (Roberts et al, 1994;Dear et al, 1995).…”

Section: Aberrant Protein Expression In T-cell Acute Lymphoblastic Lementioning

confidence: 99%

Mechanisms of transcription factor deregulation in lymphoid cell transformation

2007

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Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG)

Cited by 74 publications

References 35 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

Mechanisms of transcription factor deregulation in lymphoid cell transformation

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