The Mir-17-92 Cluster Contributes to MLL Leukemia through the Repression of PKNOX1, a MEIS1 Competitor

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 877-877
Author(s):  
Yousaf A Mian ◽  
Nancy J. Zeleznik-Le
Keyword(s):  
Target Genes ◽  
Hox Genes ◽  
Regulatory Mechanism ◽  
Conflicts Of Interest ◽  
Chromosome Translocation ◽  
Transcriptional Elongation ◽  
Terminal Portion ◽  
Partner Protein ◽  
Carboxy Terminal

Abstract Leukemias which arise as a result of translocations between the MLL gene and one of more than 80 different partner genes have a relatively poor prognosis. As a result of chromosome translocation, the carboxy-terminal portion of MLL containing the H3K4 methyltransferase domain is replaced by partner protein domains. In most cases this causes constitutive recruitment of transcriptional elongation machinery to MLL target genes. Downstream targets of MLL are aberrantly upregulated and include developmentally important HOX genes and MEIS1, as well as multiple microRNAs. Here we examine the contribution of specific miRNAs in the miR-17-92 cluster to MLL leukemia through the use of custom antagomiR oligonucleotides. Combinatorial treatment with antagomiRs against miR-17 and miR-19a dramatically reduce colony forming ability of MLL-fusion containing cells, but not non-MLL AML controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17 and miR-19a. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX proteins. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of Pknox1 to leukemia in a murine MLL-AF9 model. Collectively, these data implicate the miR-17-92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia. This approach represents a paradigm where targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen. Disclosures No relevant conflicts of interest to declare.

The Ability of Fibrinogens, FI and FII, to Support ADP- Induced Platelet Aggregation

1983 ◽  
Vol 50 (02) ◽  
pp. 527-529 ◽  
Author(s):  
H M Phillips ◽  
A Mansouri ◽  
C A Perry
Keyword(s):  
Platelet Aggregation ◽  
Terminal Portion ◽  
Hepes Buffer ◽  
Carboxy Terminal

SummaryFibrinogen plays an integral part in ADP-induced platelet aggregation. Controversy exists in regard to the role of the carboxy termini of fibrinogen Aa chains in this reaction. We have attempted to clarify this problem in view of the availability of a highly purified FII fibrinogen fraction. Kabi fibrinogen or its purified fractions FI, FII and FIII-IV-V were added to washed platelets in the presence of Tyrode-HEPES buffer pH 7.4. Aggregation was initiated by the addition of calcium and ADP. These fibrinogen fractions equally promoted ADP-induced platelet aggregation. The major difference among these fractions is in their Aα chains. The FI fraction contains intact Aα chains while FII and FIH-IV-V fractions have one and two partially degraded Aα chains at the carboxy terminal portion respectively. We conclude that the carboxy terminal portion of the Aα chain does not play an important role in promoting ADP-induced platelet aggregation.

Targeting Menin-MLL Interaction to Inhibit MLL Fusion Oncoproteins in Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2497-2497
Author(s):  
Jolanta Grembecka ◽  
Shihan He ◽  
Aibin Shi ◽  
Trupta Purohit ◽  
Andrew G. Muntean ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Acute Leukemia ◽  
Protein Interaction ◽  
Fusion Proteins ◽  
Target Genes ◽  
Hox Genes ◽  
Conflicts Of Interest ◽  
Acute Leukemias ◽  
In Vivo Models ◽  
Novel Therapeutic

Abstract Abstract 2497 Chromosomal translocations that affect the MLL (Mixed Lineage Leukemia) proto-oncogene occur in aggressive acute leukemias, both in children and adults. Fusion of MLL to one of more than 50 partner genes results in generation of the MLL fusion oncoprotein, which upregulates expression of HOX genes required for normal hematopoiesis, and ultimately leads to the development of acute leukemia. Patients harboring translocations of MLL gene suffer from very aggressive leukemias and respond poorly to available therapies, emphasizing the urgent need for novel therapeutic treatments. All oncogenic MLL fusion proteins have a preserved N-terminal fragment of MLL that interacts with menin, a tumor suppressor protein encoded by MEN1 (Multiple Endocrine Neoplasia 1) gene. Importantly, the menin-MLL fusion protein interaction is critical to the leukemogenic activity of MLL fusion proteins and misregulation of HOXA9 genes, and therefore it represents a valuable molecular target for therapeutic intervention. Selective targeting of the protein-protein interaction between menin and MLL fusion proteins with small molecules could block the oncogenic activity of MLL fusion proteins and inhibit development of acute leukemia. To identify small molecule inhibitors of the menin-MLL interaction we have performed a High Throughput Screen of 350,000 compounds using a collection of biochemical assays and biophysical methods. This resulted in several classes of compounds that specifically bind to menin and inhibit the menin-MLL interaction both in vitro and in human cells. We then applied medicinal chemistry approaches to develop analogues of selected lead candidates, resulting in very potent compounds that inhibit the menin-MLL interaction with nanomolar affinities. To evaluate potency, specificity and mechanism of action of these compounds we used a broad collection of cellular assays. These compounds selectively inhibit proliferation of the MLL leukemia cells, strongly induce apoptosis and differentiation of these cells. Importantly, these compounds substantially downregulate expression of HOXA9 and MEIS1 genes that are downstream targets of MLL fusion proteins required for their leukemogenicity, and they also deplete the menin-MLL fusion protein complex from the target genes. Furthermore, the compounds that we developed specifically inhibit the MLL fusion protein mediated oncogenic transformation. All these effects closely recapitulate the effects observed upon acute loss of menin or disruption of the menin-MLL fusion protein interaction using genetic manipulations, demonstrating highly specific mode of action for these compounds. Our current efforts are focused to assess the effect of these compounds in in vivo models of MLL leukemia and evaluate their utility as future drug candidates for acute leukemias. This may provide a novel therapeutic approach for the treatment of very aggressive leukemias with MLL translocations. Disclosures: No relevant conflicts of interest to declare.

MLL Fusion Protein Driven AML Is Selectively Inhibited by Targeted Disruption of the MLL-PAFc Interaction

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 56-56 ◽  
Author(s):  
Andrew G. Muntean ◽  
Eric M Granowicz ◽  
Jay L. Hess
Keyword(s):  
Fusion Protein ◽  
Colony Formation ◽  
Fusion Proteins ◽  
Target Genes ◽  
Hox Genes ◽  
Conflicts Of Interest ◽  
Dominant Negative ◽  
Conditional Knockout ◽  
Transformed Cells ◽  
Mouse Bone Marrow

Abstract Abstract 56 Balanced chromosomal translocations of the MLL gene located on chromosome 11q23 result in the expression of a chimeric fusion proteins with enhanced transcriptional activity. The HOX genes and their co-factors, such as MEIS1 and PBX2, are critical downstream targets of MLL fusion proteins and essential for transformation. Previously we showed MLL fusion proteins are critically dependent on a direct interaction with the RNA Pol II Associated Factor complex (PAFc). PAFc is a protein complex important for the initiation, elongation and termination of transcription. It is also necessary for histone H2B K120 mono-ubiquitination through the direct recruitment of the BRE1/RAD6 E3 ubiquitin ligase complex. MLL fusion proteins make two direct contacts with the PAF1 and CTR9 subunits of the PAFc that are crucial for MLL fusion protein mediated transformation. Deletion of regions of MLL that interact with PAFc abrogates AML in mouse bone marrow transplantation assays. Here we tested the general requirement for PAFc in AML using a conditional knockout mouse model of one component of PAFc, Cdc73. These studies show that PAFc is necessary for growth of both E2A-HLF and MLL-AF9 transformed cells. Excision of Cdc73 leads to decreased expression of the MLL target genes Hoxa9 and Meis1, decreased colony formation and decreased proliferation of leukemic blasts and ultimately apoptosis. We then performed chromatin immunoprecipitation assays to assess the binding of PAFc and MLL to target loci with and without Cdc73. Excision of Cdc73 leads to a rapid decrease in association of PAFc as well as MLL fusion proteins and wild type MLL at target loci confirming that proper targeting of MLL fusion proteins requires PAFc. A decrease in H3K4me3 and H2Bub is also observed and consistent with a role of PAFc in the deposition of these epigenetic marks. We then sought to disrupt the MLL-PAFc interaction through expression of a small 40 amino acid fragment of MLL that interacts with the PAF1 subunit of PAFc. As the MLL-PAFc interaction involves interactions between MLL and both CTR9 and PAF1, it was unknown whether targeting one interaction site would be sufficient to disrupt transformation. Indeed, expression of the short fragment encompassing the pre-CxxC region of MLL acts as a dominant negative and disrupts the MLL-PAFc interaction, significantly decreasing Hox gene expression, colony formation and cell proliferation of MLL-AF9 transformed cells. Importantly, expression of the MLL fragment selectively inhibited MLL fusion mediated leukemic transformation and cell growth while the growth and proliferation of E2A-HLF cells is unaffected. Together these data show that targeting the MLL-PAFc interaction with a small MLL fragment can act as a dominant negative and selectively inhibit the growth of AML cells transformed with MLL fusion proteins. These data also suggest the MLL-PAF1 interaction surface is a promising region for therapeutic targeting. Disclosures: No relevant conflicts of interest to declare.

Mechanisms of Transcriptional Regulation and Transformation by HOXA9

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-30-SCI-30
Author(s):  
Jay L. Hess ◽  
Cailin Collins ◽  
Joel Bronstein ◽  
Yuqing Sun ◽  
Surya Nagaraja
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
A Genome ◽  
The Impact

Abstract Abstract SCI-30 HOXA9 plays important roles in both development and hematopoiesis and is overexpressed in more than 50 percent of acute myeloid leukemias (AML). Nearly all cases of AML with mixed lineage leukemia (MLL) translocations show increased HOXA9 expression, as well as cases with mutation of the nucleophosmin gene NPM1, overexpression of CDX2, and fusions of NUP98. In most cases, upregulation of HOXA9 is accompanied by upregulation of its homeodomain-containing cofactor MEIS1, which directly interacts with HOXA9. While HOXA9 alone is sufficient for transformation of hematopoietic stem cells in culture, the addition of MEIS1 increases the transformation efficiency and results in rapidly fatal leukemias in transplanted animals. Despite the crucial role that HOXA9 plays in development, hematopoiesis, and leukemia, its transcriptional targets and mechanisms of action are poorly understood. We have used ChIP-seq to identify Hoxa9 and Meis1 binding sites on a genome-wide level in myeloblastic cells, profiled their associated epigenetic modifications, identified the target genes regulated by HOXA9 and identified HOXA9 interacting proteins. HOXA9 and MEIS1 cobind at hundreds of promoter distal, highly evolutionarily conserved sites showing high levels of histone H3K4 monomethylation and CBP/P300 binding. These include many proleukemogenic gene loci, such as Erg, Flt3, Myb, Lmo2, and Sox4. In addition, HOXA9 binding sites overlap a subset of enhancers previously implicated in myeloid differentiation and inflammation. HOXA9 binding at enhancers stabilizes association of MEIS1 and lineage-restricted transcription factors, including C/EBPα, PU.1, and STAT5A/B thereby promoting CBP/p300 recruitment, histone acetylation, and transcriptional activation. Current efforts are focused on using both biochemical and genetic approaches to assess the role of HOXA9 “enhanceosome” components C/EBPα, PU.1, and STAT5A/B in transcriptional regulation and leukemogenesis. Studies to date suggest that C/EBPα and PU.1 binding can occur in the absence of HOXA9/MEIS1, supporting a model in which these proteins act as pioneer transcription factors for establishment of poised, but not activated, HOXA9-regulated enhancers. Work is under way to assess the impact of high-level HOXA9 and MEIS1 on enhanceosome assembly and the role of recruitment of transcriptional coactivators involved in target gene up- or downregulation, including histone acetyltransferases and chromatin remodeling complexes. Collectively, our findings suggest that HOXA9-regulated enhancers are a fundamental mechanism of HOX-mediated transcription in normal development that is deregulated in leukemia. Disclosures: No relevant conflicts of interest to declare.

Role Of Histone Deacetylase 6 (HDAC6) In The Modulation Of STAT Pathways and Immune Function Of APCs

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1032-1032
Author(s):  
Maritza Lienlaf ◽  
Patricio Perez-Villarroel ◽  
Fengdong Cheng ◽  
Calvin K. Lee ◽  
Jorge Canales ◽  
...  
Keyword(s):  
Cell Lines ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Cell Cycle Control ◽  
Critical Role ◽  
Histone Deacetylase 6 ◽  
Histone Modifiers

Abstract Histone deacetylases (HDACs), originally discovered as histone modifiers are now proposed as important regulators of non-chromatin related processes, including the regulation of cellular pathways involved in the production of anti- and pro-inflammatory cytokines and the subsequent function of antigen-presenting cells (APCs). We have recently identified HDAC6 as a positive regulatory factor in the production of IL-10. However, the participation of this HDAC in other immune related cellular processes remains unknown. In this work we present evidence of the important role of HDAC6 in the modulation of the JAK/STAT pathway through the IL-6 regulation. We generated knockdown cell lines of HDAC6 (HDAC6KD) and non-target (NT) cells as a control in RAW264.7 murine macrophages using lentiviral shRNA. Two HADC6KD and two NT cell lines were treated with LPS or were left untreated and then analyzed by microarray. In HDAC6KD cells we found 1542 genes were down-regulated and 775 up-regulated in HDAC6KD cells. Their ontology distribution revealed significant changes in immune-related and apoptosis/cell cycle control genes. Importantly, we observed that most STAT3 and SP1 target genes were down regulated in HDAC6KD cells, suggesting the participation of HDAC6 in the regulation of these two transcription factors. Further analysis evidenced that the phosphorylation of STAT3 and the acetylation of Sp1 were diminished in HDAC6KD cells when compared against control cells. Chromatin immuneprecipitacion (CHIP) assays indicate that this particular effect of abrogation of HDAC6 involved histone modifications at the IL-6 promoter level, and more importantly, the recruitment of STAT3 and Sp1 to the IL-6 promoter was abrogated. Then, we analyzed the relevance of these findings by studying the tolerogenic JAK/STAT signaling pathway, which is known to be activated by IL-6 and critical in the final outcome of APCs in response to stimuli. Our observations included a complete abrogation in the phosphorylation of JAK2 and STAT3 proteins in HDAC6KD cells in response to LPS, which was reverted when these cells were treated with exogenous IL-6. Our final results demonstrate a critical role of HDAC6 in the modulation of IL-6 and the potential role of HDAC6 in the regulation of the JAK/STAT3 pathway. In addition HDAC6 is a regulator of SP1 and STAT3 target genes. These findings provide insight into the molecular mechanisms controlling the immunogenicity of APCs, supporting the use of HDAC6 inhibitors to enhance immune activation, and positioning HDAC6 as a potential therapeutic target. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interaction between P-TEFb and the C-Terminal Domain of RNA Polymerase II Activates Transcriptional Elongation from Sites Upstream or Downstream of Target Genes

2002 ◽  
Vol 22 (1) ◽  
pp. 321-331 ◽  
Author(s):  
Ran Taube ◽  
Xin Lin ◽  
Dan Irwin ◽  
Koh Fujinaga ◽  
B. Matija Peterlin
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Elongation Factor ◽  
Transcriptional Elongation ◽  
Cyclin T1 ◽  
Positive Transcription Elongation Factor ◽  
Terminal Domain ◽  
Activation Of Transcription

ABSTRACT Transcriptional elongation by RNA polymerase II (RNAPII) is regulated by the positive transcription elongation factor b (P-TEFb). P-TEFb is composed of Cdk9 and C-type cyclin T1 (CycT1), CycT2a, CycT2b, or CycK. The role of the C-terminal region of CycT1 and CycT2 remains unknown. In this report, we demonstrate that these sequences are essential for the activation of transcription by P-TEFb via DNA, i.e., when CycT1 is tethered upstream or downstream of promoters and coding sequences. A histidine-rich stretch, which is conserved between CycT1 and CycT2 in this region, bound the C-terminal domain of RNAPII. This binding was required for the subsequent expression of full-length transcripts from target genes. Thus, P-TEFb could mediate effects of enhancers on the elongation of transcription.

scholarly journals BCOR Regulates Cell Fate Transition, Myeloid Differentiation and Leukaemogenesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3907-3907 ◽  
Author(s):  
Lev M Kats ◽  
Madison J Kelly ◽  
Gareth Gregory ◽  
Ricky W Johnstone ◽  
Stephin J Vervoort
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Haematopoietic Stem Cell ◽  
Myeloid Differentiation ◽  
Transcriptional Networks ◽  
Cell Fate Decisions ◽  
Myeloid Progenitors

Abstract Stem cell self-renewal and lineage specification are highly dynamic and tightly controlled processes that are essential for normal haematopoiesis and are dysregulated in cancer. The X-linked BCL6 Corepressor (BCOR) gene encodes a protein that is widely expressed across adult human tissues and is a component of a non-canonical Polycomb repressive complex 1 (PRC1). The BCOR gene is recurrently mutated in various malignant and non-malignant blood disorders, and we and others have recently provided experimental evidence that BCOR has cell-context dependent functions in regulating the proliferation, differentiation and survival of haematopoietic cells. To comprehensively examine the role of BCOR in haematopoiesis in vivo we used a conditional mouse model that mimics the truncating mutations observed in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Using stem and progenitor populations isolated ex vivo we comprehensively analysed the role of BCOR in regulating gene expression, modifying chromatin and altering genome architecture. We demonstrate that BCOR has a pivotal role in down-regulating haematopoietic stem cell (HSC) associated transcriptional networks during the transition from multi-potent stem cells to lineage-committed myeloid progenitors. Inactivation of Bcor in HSCs results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Mechanistically, Bcor regulates a subset of PRC1-target genes including key HSC super-enhancer-linked transcription factors that are normally down-regulated during myeloid differentiation. We used CRISPR/Cas9 to explore the function of Bcor target genes and identified those that are necessary for the proliferation of Bcor mutant leukaemic cells. This study provides a comprehensive mechanistic understanding of how BCOR regulates cell fate decisions and contributes to the development of leukaemia. Disclosures No relevant conflicts of interest to declare.

Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3163-3174 ◽  
Author(s):  
D.J. Roberts ◽  
R.L. Johnson ◽  
A.C. Burke ◽  
C.E. Nelson ◽  
B.A. Morgan ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Target Genes ◽  
Hox Genes ◽  
Ectopic Expression ◽  
Secreted Protein ◽  
Gut Development ◽  
Visceral Mesoderm ◽  
Homologous Genes ◽  
Inductive Signal

Reciprocal inductive signals between the endoderm and mesoderm are critical to vertebrate gut development. Sonic hedgehog encodes a secreted protein known to act as an inductive signal in several regions of the developing embryo. In this report, we provide evidence to support the role of Sonic hedgehog and its target genes Bmp-4 and the Abd-B-related Hox genes in the induction and patterning the chick hindgut. Sonic is expressed in the definitive endoderm at the earliest stage of chick gut formation. Immediately subjacent to Sonic expression in the caudal endoderm is undifferentiated mesoderm, later to become the visceral mesoderm of the hindgut. Genes expressed within this tissue include Bmp-4 (a TGF-beta relative implicated in proper growth of visceral mesoderm) and members of the Abd-B class of Hox genes (known regulators of pattern in many aspects of development). Using virally mediated misexpression, we show that Sonic hedgehog is sufficient to induce ectopic expression of Bmp-4 and specific Hoxd genes within the mesoderm. Sonic therefore appears to act as a signal in an epithelial-mesenchymal interaction in the earliest stages of chick hindgut formation. Gut pattern is evidenced later in gut morphogenesis with the presence of anatomic boundaries reflecting phenotypically and physiologically distinct regions. The expression pattern of the Abd-b-like Hox genes remains restricted in the hindgut and these Hox expression domains reflect gut morphologic boundaries. This finding strongly supports a role for these genes in determining the adult gut phenotype. Our results provide the basis for a model to describe molecular controls of early vertebrate hindgut development and patterning. Expression of homologous genes in Drosophila suggest that aspects of gut morphogenesis may be regulated by similar inductive networks in the two organisms.

MYC Regulation Via the LIN28B/Let-7 Axis in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1755-1755
Author(s):  
Salomon Manier ◽  
John Powers ◽  
Antonio Sacco ◽  
Siobhan Glavey ◽  
Daisy Huynh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Sequencing ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Scid Mice ◽  
Cellular Reprogramming ◽  
Western Blots

Abstract Background. LIN28B regulates developmental processes and cellular reprogramming by suppressing let-7 microRNAs (miRNAs). A role for LIN28B has been reported in cancers, however the LIN28B/let-7 axis has not been studied in multiple myeloma (MM). Methods. LIN28B level expression in MM patients was studied using previously published gene expression profiling (GEP) datasets. Knockdown (KD) of LIN28B was performed on MM cell lines (U266, MOLP-8) using 2 shRNA and validated using 2 sgRNA by CRISPR knockout (KO). Downstream regulations were assessed by qRT-PCR and western blots, as well as RNA sequencing. For RNA sequencing, control and Lin28B CRISPR cells were used for library preparation (NEBNext kit) and sequencing on a HiSeq 2000. Proliferation of KD and KO cells were evaluated in vitro and in vivo in a xenograft mouse model. An LNA-GapmeR technology was used to develop a let-7 mimic in vivo in SCID mice. Findings. Two independent GEP datasets (GSE16558; GSE2658) were analyzed for LIN28B expression, showing a significantly higher level in MM patients compared to healthy controls. In addition, high LIN28B levels correlated with a shorter overall survival (p = 0.0226), along with an enrichment of let-7 target genes by Gene Set Enrichment Analyses (GSEA). LIN28B KD cells had a significantly increased expression level of let-7 family members and were associated with down-regulation of let-7 target genes Myc and Ras at the protein level. We further confirmed downstream regulation of MYC and RAS in a LIN28B CRISPR KO model in MM cells (MOPL-8). We next validated the role of LIN28B in MM in vivo by using a xenograft tumor model showing a decreased tumor burden in LIN28B KD mice compared to scramble control (p =0.0045). In addition, we performed a RNA sequencing from the CRISPR LIN28B KO and control cells and observed a central role by GSEA for both MYC and E2F cell cycle pathways in LIN28B-engineered cells. LIN28B activity in regulating MYC and cell proliferation was further defined to be dependent on let-7 by performing a rescue experiment in MM1S cells. Moreover, we explored the possibility to therapeutically regulate MYC expression through let-7 with an LNA-GapmeR containing a let-7b mimic, in vivo, and showed that high levels of let-7 expression represses tumor growth in SCID mice by regulating MYC expression compared to control GapmeR treated mice (p = 0.0026). Conclusions. These findings reveal the essential role of LIN28B/let-7 in regulating two essential oncogenic pathways in MM, MYC and RAS. Interference with this pathway may represent an efficient option for targeting MYC in cancer. Disclosures No relevant conflicts of interest to declare.

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