Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patients

Trentin, Luca; Giordan, Marco; Dingermann, Theo; Basso, Giuseppe; Kronnie, Geertruy te; Marschalek, Rolf

doi:10.1111/j.1600-0609.2009.01305.x

Cited by 54 publications

(95 citation statements)

References 49 publications

(90 reference statements)

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“…We have also compared our GEP with the GEP reported by Trentin et al [35] and Stam et al [19]. As shown in Supplementary information, Figure 5SA, few genes were commonly found regulated not only among the three studies, but also between Trentin et al [35] and Stam et al [19] (< 19 genes).…”

Section: Discussionmentioning

confidence: 80%

“…As shown in Supplementary information, Figure 5SA, few genes were commonly found regulated not only among the three studies, but also between Trentin et al [35] and Stam et al [19] (< 19 genes). Interestingly, Meis1, a key Hox co-factor implicated in leukemogenesis, was found upregulated in the three studies.…”

Section: Discussionmentioning

confidence: 84%

“…Interestingly, Stam et al [19] have reported the existence of two distinct subgroups among t(4;11)-positive infant ALL cases characterized by the absence or presence of HOXA expression, with those patients lacking HOXA expression being at extreme high risk of disease relapse. In contrast, Trentin et al [35] have recently questioned the function of activated Hox gene expression in t(4;11)-positive infant ALL. These patients were sub-divided into Hox gene expression high vs low and no biological/clinical relevance could be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…It is crucial to be aware that these two GEP studies based on primary patient samples are conceptually distinct. Trentin et al [35] compared MLL-AF4+ infant B-ALL with normal bone marrow whereas Stam et al [19] compared MLL-AF4+ infant B-ALL with other MLL germline ALL, indicating that because gene expression data has been normalized against different primary samples, caution must be taken when comparing independent GEP studies. Additionally, caution is also required when comparing independent GEP studies mediated by MLL-AF4 because secondary oncogenic events already present in patient samples [19,35] may contribute along with MLL-AF4 to the gene expression signatures observed in these clinical samples, whereas in our transgenic hESC model we studied the impact of gene expression of MLL-AF4 on its own (in a nonleukemic background).…”

Section: Discussionmentioning

confidence: 99%

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A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

Bueno¹,

Montes²,

Melén³

et al. 2012

Cell Res

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The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well established that MLL-AF4 arises prenatally during human development, its effects on hematopoietic development in utero remain unexplored. We have created a human-specific cellular system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Functional studies, clonal analysis and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. MLL-AF4 acts as a global transcriptional activator and a positive regulator of homeobox gene expression in hESCs. Functionally, MLL-AF4 enhances the specification of hemogenic precursors from hESCs but strongly impairs further hematopoietic commitment in favor of an endothelial cell fate. MLL-AF4 hESCs are transcriptionally primed to differentiate towards hemogenic precursors prone to endothelial maturation, as reflected by the marked upregulation of master genes associated to vascular-endothelial functions and early hematopoiesis. Furthermore, we report that MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells. This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes, known to arise prenatally, regulate human embryonic hematopoietic specification.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

Bueno¹,

Montes²,

Melén³

et al. 2012

Cell Res

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“…15 The HOXA cluster genes, and especially HOXA4, HOXA5, HOXA9 and HOXA10, are over-expressed in MLL-rearranged ALL. [16][17][18] However, aberrant expression of HOXA genes is not restricted to MLL-rearranged precursor B-ALL cases and has also been reported to occur in T-ALL patients carrying MLL-or HOXA-rearrangements e.g. inversion of chromosome 7, or fusion products including CALM-AF10 and SET-NUP214.…”

mentioning

confidence: 99%

Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia

Schotte¹,

Lange-Turenhout²,

Stumpel³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundDeregulation of microRNA may contribute to hematopoietic malignancies. is highly expressed in MLL-rearranged leukemia and has been shown to be activated by MLL and MLL-fusion genes. Design and MethodsIn order to determine whether high expression of miR-196b is restricted to MLL-rearranged leukemia, we used quantitative stem-loop reverse transcriptase polymerase chain reaction to measure the expression of this microRNA in 72 selected cases of pediatric acute lymphoblastic leukemia i.e. MLL-rearranged and non-MLL-rearranged precursor B-cell and T-cell acute lymphoblastic leukemias. We also determined the expression of HOXA-genes flanking miR-196 by microarray and real-time quantitative polymerase chain reaction. Furthermore, we used CpG island-arrays to explore the DNA methylation status of miR-196b and HOXA. ResultsWe demonstrated that high expression of miR-196b is not unique to MLL-rearranged acute lymphoblastic leukemia but also occurs in patients with T-cell acute lymphoblastic leukemia patients carrying CALM-AF10, SET-NUP214 and inversion of chromosome 7. Like MLLrearrangements, these abnormalities have been functionally linked with up-regulation of HOXA. In correspondence, miR-196b expression in these patients correlated strongly with the levels of HOXA family genes (Spearman's correlation coefficient ≥ 0.7; P≤0.005). Since miR196b is encoded on the HOXA cluster, these data suggest co-activation of miR-196b and HOXA genes in acute lymphoblastic leukemia. Up-regulation of miR-196b coincides with reduced DNA methylation at CpG islands in the promoter regions of miR-196b and the entire HOXA cluster in MLL-rearranged cases compared to in cases of non-MLL precursor B-cell acute lymphoblastic leukemia and normal bone marrow (P<0.05), suggesting an epigenetic origin for miR-196b over-expression. Although patients with MLL-rearranged acute lymphoblastic leukemia are highly resistant to prednisolone and L-asparaginase, this resistance was not attributed to miR-196b expression. ConclusionsHigh expression of miR-196b is not exclusively MLL-driven but can also be found in other types of leukemia with aberrant activation of HOXA genes. Since miR-196b has been shown by others to exert oncogenic activity in bone marrow progenitor cells, the findings of the present study imply a potential role for miR-196b in the underlying biology of all HOXA-activated leukemias.Key words: miR-196b, HOXA, acute lymphoblastic leukemia.Citation: Schotte D, Stumpel DJPM, Stam RW, Meijerink JPP, Pieters R, is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia. Haematologica 2010;95(10):1675-1682. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Expression of miR-196b is not exclusively MLL-driven

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Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Somers

Kosciolek

Bongers

et al. 2019

Intl Journal of Cancer

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Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy‐resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL‐rearranged (MLL‐r) leukemia that can be combined with established chemotherapeutics to decrease treatment‐related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL‐r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL‐r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL‐r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well‐tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL‐r acute myeloid leukemia model and in patient‐derived xenograft models of MLL‐r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL‐r leukemia.

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Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patients

Abstract: A yet homogeneous leukemia entity was further subdivided, based on distinct genetic properties. This approach provided a simplified way to obtain robust and disease-specific gene signatures even in smaller cohorts.

Cited by 54 publications

References 49 publications

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

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