The AF4·MLL fusion protein is capable of inducing ALL in mice without requirement of MLL·AF4

Bursen, A; Schwabe, Karen; Rüster, Brigitte; Henschler, Reinhard; Ruthardt, Martin; Dingermann, Theo; Marschalek, Rolf

doi:10.1182/blood-2009-06-229542

Cited by 144 publications

(169 citation statements)

References 36 publications

(42 reference statements)

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“…Moreover, transduction of murine hematopoietic progenitor/stem cells with a retrovirus encoding the AF4-MLL fusion protein resulted in development of proB acute lymphoblastic leukemia in mice. 8 Together, these findings imply that both t(4;11) fusion proteins, MLL-AF4 and AF4-MLL, contribute to the malignant processes in t(4;11) leukemia. Therefore, we decided to purify the AF4-MLL complex in order to gain insights into its pathological function.…”

Section: Introductionmentioning

confidence: 84%

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

et al. 2010

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Expression of the AF4-MLL fusion protein in murine hematopoietic progenitor/stem cells results in the development of proB acute lymphoblastic leukemia. In this study, we affinity purified the AF4-MLL and AF4 protein complexes to elucidate their function. We observed that the AF4 complex consists of 11 binding partners and exhibits positive transcription elongation factor b (P-TEFb)-mediated activation of promoter-arrested RNA polymerase (pol) II in conjunction with several chromatin-modifying activities. In contrast, the AF4-MLL complex consists of at least 16 constituents including P-TEFb kinase, H3K4 me3 and H3K79 me3 histone methyltransferases (HMT), a protein arginine N-methyltransferase and a histone acetyltransferase. These findings suggest that the AF4-MLL protein disturbs the fine-tuned activation cycle of promoter-arrested RNA Pol II and causes altered histone methylation signatures. Thus, we propose that these two processes are key to trigger cellular reprogramming that leads to the onset of acute leukemia.

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Section: Introductionmentioning

confidence: 84%

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

et al. 2010

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“…Mounting evidence indicates that MLL-AF4 is the initiating leukemogenic event with an in utero origin [5,25]. However, an understanding of potential changes in early hematopoietic development mediated by MLL-AF4 is lacking, despite of the recent advances by Krivtsov et al [8] and Bursen et al [26], current mouse models do not accurately recapitulate either the disease phenotype or latency [6,8,9]. Furthermore, studies using primary cells from MLL-AF4 patients are incapable of addressing the developmental genesis of the hematopoietic system.…”

Section: Discussionmentioning

confidence: 99%

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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“…Most of our understanding of transformation by MLL-AF4 has come from murine models [2][3][4]26,27 and human stem cell systems. 1,[28][29][30][31][32][33] These have provided important insights into the likely mode of action of MLL-AF4, but the in vivo leukemias produced in these studies do not recapitulate the actual human disease phenotype and latency, and therefore MLL-AF4 leukemogenesis remains particularly difficult to model.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that in order to develop a bona fide MLL-AF4 model by which to further understand the disease pathogenesis and to screen novel small-molecule compounds, additional oncogenic events such as FLT3 constitutive activation 8 or the derivative AF4-MLL seem to be required to develop ALL. 26 The very high FLT3 mean expression in MLL-AF4 þ ALL patients coupled to the high variability (3.5-to 110-fold expression) suggests the possibility that the FLT3 expression level may have a prognostic significance in MLL-AF4 þ ALL. To analyze the prognosis of our ALL cohort in relation to FLT3 expression, the median FLT3 expression was used as the cut-off value to divide patients into two subgroups expressing high or low levels of FLT3.…”

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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The AF4·MLL fusion protein is capable of inducing ALL in mice without requirement of MLL·AF4

Cited by 144 publications

References 36 publications

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

The leukemogenic AF4–MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

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

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

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