Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Park, Sun Mi; Gönen, Mithat; Vu, Ly; Minuesa, Gerard; Tivnan, Patrick; Barlowe, Trevor; Taggart, James; Lu, Yuheng; Deering, Raquel P.; Hacohen, Nir; Figueroa, María E.; Paietta, Elisabeth; Fernandez, Hugo F.; Tallman, Martin S.; Melnick, Ari; Levine, Ross L.; Leslie, Christina; Lengner, Christopher J.; Kharas, Michael G.

doi:10.1172/jci78440

Cited by 94 publications

(126 citation statements)

References 76 publications

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“…MSI2 was for the first time linked to roles in supporting stem cell gene signatures and disease progression in myelodysplastic syndromes (MDS) (58). Overall, these and other studies have identified a large number of targets of Musashi-dependent expression, which besides those mentioned above include Hoxa9, Myc, Ikzf2 (53), NF-YA, a regulator of the proteasome (59), and Jagged1 (54). Musashi proteins have also recently been reported influence expression of lin28A, joining other studies connecting these proteins to control of cancer-associated micro-RNAs (miRs) (60,61).…”

Section: Demonstration Of Driver Roles For Musashi Expression In Oncomentioning

confidence: 81%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

221

240

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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as regulators of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers, glioblastoma, and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target.

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Section: Demonstration Of Driver Roles For Musashi Expression In Oncomentioning

confidence: 81%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

221

240

View full text Add to dashboard Cite

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“…However, we did not determine the underlying mechanism of MSI2’s promotion of PDAC growth and metastasis. Researchers have demonstrated that elevated expression of MSI2 could interact with and cause the retention of efficient translation of a series of oncogenic factors, including MYC, HOXA9, cyclin D1, and Cdk2 (5, 39). Also, MSI2 is reported to activate Wnt and Notch signaling pathways (9, 31).…”

Section: Discussionmentioning

confidence: 99%

“…Musashi 2 (MSI2) is one of the two members of the Musashi family of RNA-binding proteins, which participate in posttranscriptional regulation by binding to specific mRNAs (4, 5). Researchers have shown that the two MSIs play critical roles in proliferation and differentiation of stem cells of the hematopoietic and nervous systems (4, 6).…”

Section: Introductionmentioning

confidence: 99%

The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer

Guo

Cui

Quan

et al. 2017

Clinical Cancer Research

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Purpose Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the present study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway. Experimental Design MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biologic functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain-and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods. Results MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC. Conclusions Lost expression of KLF4, a transcriptional repressor of MSI2, results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis.

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“…These efforts have predominantly centered around intrinsic signals such as β-catenin (Wang et al, 2010), PI3K (Doepfner et al, 2007; Xu et al, 2003), NFκB (Guzman et al, 2001), MAPK (Milella et al, 2001) and Msi2 (Kwon et al, 2015; Park et al, 2015). However, the specific molecules that integrate signal reception from the microenvironment remain relatively unexplored.…”

Section: Discussionmentioning

confidence: 99%

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

et al. 2016

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SUMMARY Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with inhibitors such as CD98-antibodies may be a valuable therapeutic approach for adults and children with this disease.

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Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Cited by 94 publications

References 76 publications

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

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