Gene expression profiling–based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants

Stam, Ronald W.; Schneider, Pauline; Hagelstein, Jill; Linden, Marieke H. van der; Stumpel, Dominique J.P.M.; Menezes, Renée X. de; Lorenzo, Paola De; Valsecchi, Maria Grazia; Pieters, Rob

doi:10.1182/blood-2009-07-233049

Cited by 145 publications

(188 citation statements)

References 34 publications

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“…13,[62][63][64] However, our laboratory showed that within MLL-rearranged infant ALL each type of MLL translocation is associated with a translocation-specific gene expression signature. 65 We identified a specific gene expression signature for the total group of MLL-rearranged AML cases, 12 but were also able to identify a specific signature for t(9;11)(p22;q23). 66 This indicates that, in addition to the common pathways in MLLrearranged AML, there are other pathways, which seem to be more dependent on the fusion partner of MLL.…”

Section: Epidemiology Of Mll Aberrations In Pediatric Amlmentioning

confidence: 88%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Section: Epidemiology Of Mll Aberrations In Pediatric Amlmentioning

confidence: 88%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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“…The existence of two distinct subgroups among t(4;11)-positive infant ALL cases characterized by the absence or presence of HOXA expression, and that patients lacking HOXA gene expression are at high risk of disease relapse were reported. 34 Future work should be conducted to determine whether there is any biochemical link between HOXA and FLT3 gene expression, and to decipher whether MLL-AF4 þ ALL patients at extremely high risk of relapse and very short OS represent the same cohort displaying high-level FLT3 and lacking HOXA expression, thus providing important novel Abbreviations: B-ALL, B-acute lymphoblastic leukemia; BM, bone marrow; DFS, disease-free survival; FLT3, FMS-related tyrosine kinase-3; OS, overall survival; PB, peripheral blood; WBC, white blood cell. a Variables were dichotomized based on the median value.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n ¼ 49) or T-ALL (n ¼ 5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1 þ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4 þ B-ALL but also ETV6-RUNX1 þ , BCR-ABL þ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P ¼ 0.002) and disease-free survival (DFS; 0 vs 43%; P ¼ 0.03) in MLL-AF4 þ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age414 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4 þ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4 þ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

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“…9 Recently, however, we published high-resolution gene-expression profiling data on a larger cohort of infant ALL samples, which even allowed specification of differential gene expression between distinct subtypes of infant ALL. 11 Studying these profiles, we observed that MLL-rearranged infant ALL frequently displays high-level expression of genes encoding members of the S100 protein family. For example, S100A10 and S100A4 appeared in the top50 of over-expressed genes in MLLrearranged infant ALL when compared with non-infant pediatric precursor B-ALL.…”

Section: Introductionmentioning

confidence: 95%

“…23,24 A detailed description of the processing of RNA samples and the generation of the gene expression profiles are previously described elsewhere. 11 Gene-set enrichment analysis 25 was used to evaluate enrichment of genes encoding S100 protein family members in prednisolone-resistant MLL-rearranged infant ALL samples. Supplementary Table 1 lists the gene enrichment scores for all S100 family members.…”

Section: In Vitro Prednisolone and In Vivo Prednisone Responsementioning

confidence: 99%

“…For example, S100A10 and S100A4 appeared in the top50 of over-expressed genes in MLLrearranged infant ALL when compared with non-infant pediatric precursor B-ALL. 11 Moreover, a recent paper by Qazi et al 12 demonstrated that in their gene-expression profiling analyses comparing ALL in infants and non-infants, over-expression of both S100A8 and S100A9 was highly characteristic for infant ALL cells. Intrigued by these observations, we set out to explore the meaning of this phenomenon, and found that the expression of S100 family members often is discriminative between prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL samples.…”

Section: Introductionmentioning

confidence: 99%

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Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

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MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca 2 þ fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca 2 þ and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca 2 þ levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca 2 þ fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.Leukemia ( Keywords: prednisolone resistance; S100A8 and S100A9; calcium signaling; MLL-rearranged infant leukemia INTRODUCTIONSince the early 1960s, treatment results for childhood acute lymphoblastic leukemia (ALL) began to improve steadily and continued to progress ever since. Consequently, the survival chances for childhood ALL, in general, nowadays exceed 85%. 1 Unfortunately, this tremendous step forward has not been equally beneficial for all patients. This is especially true for infants (o1 year of age) with ALL carrying leukemia-specific chromosomal translocations involving the MLL gene, which occur in B80% of the infant ALL cases. 2,3 Depending on the treatment protocol, survival chances for MLL-rearranged infant ALL patients are at best B40%. 3 Considerably contributing to this poor outcome is cellular resistance to multiple chemotherapeutic drugs, in particular to glucocorticoids like prednisone and dexamethasone, which form the cornerstone of childhood ALL treatment regimes. Prednisolone (the biologically active metabolite of prednisone) dosages needed to eliminate 50% of infant ALL cells in vitro typically are B500 --fold higher than the dosages required to eradicate similar amounts of precursor B-ALL cells from children older than one year of age (that is, non-infants). 4 Moreover, approximately 30% of infants with MLL-rearranged ALL show a poor prednisone response in vivo, compared with only B10% of non-infant pediatric precursor B-ALL cases. 5 As the in vitro prednisolone response and the prednisone response in vivo represent important prognostic factors, 6 --8 ...

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Gene expression profiling–based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants

Cited by 145 publications

References 34 publications

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

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