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A Novel Inducible Mouse Model of MLL-ENL-driven Mixed-lineage Acute Leukemia.

ABSTRACT: Previous retroviral and knock-in approaches to model human t(11;19)+ acute mixed-lineage leukemia in mice resulted in myeloproliferation and acute myeloid leukemia not fully recapitulating the human disease. The authors established a doxycycline (DOX)-inducible transgenic mouse model "iMLL-ENL" in which induction in long-term hematopoietic stem cells, lymphoid primed multipotent progenitor cells, multipotent progenitors (MPP4) but not in more committed myeloid granulocyte-macrophage progenitors led to a fully reversible acute leukemia expressing myeloid and B-cell markers. iMLL-ENL leukemic cells generally expressed lower MLL-ENL mRNA than those obtained after retroviral transduction. Disease induction was associated with iMLL-ENL levels exceeding the endogenous Mll1 at mRNA and protein levels. In leukemic cells from t(11;19)+ leukemia patients, MLL-ENL mRNA also exceeded the endogenous MLL1 levels suggesting a critical threshold for transformation. Expression profiling of iMLL-ENL acute leukemia revealed gene signatures that segregated t(11;19)+ leukemia patients from those without an MLL translocation. Importantly, B220+ iMLL-ENL leukemic cells showed a higher in vivo leukemia initiation potential than coexisting B220- cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell-of-origin and the fusion gene expression levels are both critical determinants for MLL-ENL-driven acute leukemia.

SUBMITTER: Stavropoulou V

PROVIDER: S-EPMC6745998 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Expression of MLL-ENL in hematopoietic stem cells induces mixed lineage acute leukemia

Project description:The t(11;19)(q23;p13.3) translocation leading to the expression of an MLL-ENL fusion is one of the most prevalent alterations affecting the mixed lineage leukemia 1 (MLL1) gene, mostly associated with B-cell acute lymphoblastic leukemia (ALL). Using a doxycycline (DOX)-inducible transgenic mouse model (“iMLL-ENL”) we show that direct induction or induction following transplantation of hematopoietic stem cells (HSC) but not of committed myeloid granulocyte-macrophage progenitors (GMP) leads to reversible acute mixed lineage leukemia. Disease induction was associated with iMLL-ENL levels exceeding the endogenous Mll1. iMLL-ENL leukemia was composed of small B220High cells with higher leukemia-initiating potential than co-existing larger-sized B220Low cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell-of-origin and the expression levels above Mll1/MLL1 are both critical determinants for mixed lineage leukemia induced by the MLL-ENL fusion.

2018-07-31 | GSE84988 | GEO

Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.

Project description:A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.

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The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.

Project description:MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL-driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL-driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.

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Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein.

Project description:Menin is a tumor suppressor protein that is encoded by the MEN1 (multiple endocrine neoplasia 1) gene and controls cell growth in endocrine tissues. Importantly, menin also serves as a critical oncogenic cofactor of MLL (mixed lineage leukemia) fusion proteins in acute leukemias. Direct association of menin with MLL fusion proteins is required for MLL fusion protein-mediated leukemogenesis in vivo, and this interaction has been validated as a new potential therapeutic target for development of novel anti-leukemia agents. Here, we report the first crystal structure of menin homolog from Nematostella vectensis. Due to a very high sequence similarity, the Nematostella menin is a close homolog of human menin, and these two proteins likely have very similar structures. Menin is predominantly an ?-helical protein with the protein core comprising three tetratricopeptide motifs that are flanked by two ?-helical bundles and covered by a ?-sheet motif. A very interesting feature of menin structure is the presence of a large central cavity that is highly conserved between Nematostella and human menin. By employing site-directed mutagenesis, we have demonstrated that this cavity constitutes the binding site for MLL. Our data provide a structural basis for understanding the role of menin as a tumor suppressor protein and as an oncogenic co-factor of MLL fusion proteins. It also provides essential structural information for development of inhibitors targeting the menin-MLL interaction as a novel therapeutic strategy in MLL-related leukemias.

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MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia.

Project description:The aim of this study was to better understand how mixed lineage leukemia (MLL) fusion proteins deregulate the expression of genes critical for leukemia.The transforming domain of one of the most common MLL fusion partners, AF9, was immunopurified after expression in myeloblastic M1 cells, and associating proteins were identified by mass spectrometric analysis. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction was used to determine how binding of associating proteins compare across Hoxa9 and Meis1 in cell lines with and without MLL fusion proteins and how binding is altered during gene down-regulation and differentiation.Consistent with earlier purifications of ENL and AF4 from 293 cells, the 90 amino acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10. This complex, termed elongation assisting proteins (EAPs), also contains the RNA polymerase II C-terminal domain kinase Cdk9/Cyclin T1/T2 (pTEFb) and the histone H3 lysine 79 methyltransferase Dot1L. Myeloid cells transformed by MLL fusions show higher levels and a broader distribution of EAP components at genes critical for leukemia. Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.The findings suggest that MLL fusion proteins deregulate genes critical for leukemia by excessive recruitment and impaired dissociation of EAP from target loci.

| S-EPMC3038424 | biostudies-literature

WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket.

Project description:WDR5 is a component of the mixed lineage leukemia (MLL) complex, which methylates lysine 4 of histone H3, and was identified as a methylated Lys-4 histone H3-binding protein. Here, we present a crystal structure of WDR5 bound to an MLL peptide. Surprisingly, we find that WDR5 utilizes the same pocket shown to bind histone H3 for this MLL interaction. Furthermore, the WDR5-MLL interaction is disrupted preferentially by mono- and di-methylated Lys-4 histone H3 over unmodified and tri-methylated Lys-4 histone H3. These data implicate a delicate interplay between the effector, WDR5, the catalytic subunit, MLL, and the substrate, histone H3, of the MLL complex. We suggest that the activity of the MLL complex might be regulated through this interplay.

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Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes.

Project description:A number of acute leukemias arise from fusion of the mixed lineage leukemia 1 protein (MLL) N terminus to a variety of fusion partners that have been reported to reside in one or more poorly defined complexes linked to transcription elongation through interactions with the histone H3-K79 methyltransferase DOT1 and positive transcription elongation factor b (P-TEFb). Here we first identify natural complexes (purified through fusion partners AF9, AF4, and ELL) with overlapping components, different elongation activities, and different cofactor associations that suggest dynamic interactions. Then, through reconstitution of defined, functionally active minimal complexes, we identify stable subcomplexes that, through newly defined protein-protein interactions, form distinct higher order complexes. These definitive analyses show, for example, that (i) through direct interactions with AF9 and cyclinT1, family members AF4 and AFF4 independently mediate association of P-TEFb with AF9, (ii) P-TEFb, through direct interactions, provides the link for association of ELL and ELL-associated factors 1 and 2 (EAF1 and EAF2) with AF4, and (iii) in the absence of other factors, DOT1 forms a stable complex with AF9 and does not interact with AF9•AF4•P-TEFb complexes. Finally, we show the importance of defined higher order complex formation in MLL-AF9-mediated transcriptional up-regulation and cell immortalization potential in vivo. Thus, our study provides direct mechanistic insight into the role of fusion partners in MLL fusion-mediated leukemogenesis.

| S-EPMC3179097 | biostudies-literature

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)-multiple rather than a single mechanism.

Project description:Despite manifold efforts to achieve reduced-intensity and -toxicity regimens, secondary leukemia has remained the most severe side effect of chemotherapeutic cancer treatment. Rearrangements involving a short telomeric <1 kb region of the mixed lineage leukemia (MLL) gene are the most frequently observed molecular changes in secondary as well as infant acute leukemia. Due to the mode-of-action of epipodophyllotoxins and anthracyclines, which have widely been used in cancer therapy, and support from in vitro experiments, cleavage of this MLL breakpoint cluster hotspot by poisoned topoisomerase II was proposed to trigger the molecular events leading to malignant transformation. Later on, clinical patient data and cell-based studies addressing a wider spectrum of stimuli identified cellular stress signaling pathways, which create secondary DNA structures, provide chromatin accessibility, and activate nucleases other than topoisomerase II at the MLL. The MLL destabilizing signaling pathways under discussion, namely early apoptotic DNA fragmentation, transcription stalling, and replication stalling, may all act in concert upon infection-, transplantation-, or therapy-induced cell cycle entry of hematopoietic stem and progenitor cells (HSPCs), to permit misguided cleavage and error-prone DNA repair in the cell-of-leukemia-origin.

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