In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Miller, Peter G.; Al‐Shahrour, Fátima; Hartwell, Kimberly A.; Chu, Lisa P.; Järås, Marcus; Puram, Rishi V.; Puissant, Alexandre; Callahan, Kevin P.; Ashton, John M.; McConkey, Marie; Poveromo, Luke; Cowley, Glenn S.; Kharas, Michael G.; Labelle, Myriam; Shterental, Sebastian; Fujisaki, Joji; Silberstein, Lev; Alexe, Gabriela; Al-Hajj, Muhammad; Shelton, Christopher A.; Armstrong, Scott A.; Root, David E.; Scadden, David T.; Hynes, Richard O.; Mukherjee, Siddhartha; Stegmaier, Kimberly; Jordan, Craig T.; Ebert, Benjamin L.

doi:10.1016/j.ccr.2013.05.004

Cited by 147 publications

(150 citation statements)

References 60 publications

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“…This is signifi cantly different from the currently used model systems, mainly cancer cell lines (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and might provide novel insights into mechanisms of tumor maintenance.…”

Section: Discussionmentioning

confidence: 78%

“…Unfortunately, however, this information is available for only a fraction of the mutated cancer genes. Loss-of-function experiments targeting multiple genes were extensively used to investigate tumor vulnerabilities in vivo , using either cancer cell lines or genetically engineered tumors which, however, do not refl ect the genetic diversity of human malignancies (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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The identifi cation of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the fi rst in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specifi c shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth ( ∼ 50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identifi ed genes, the Histone-lysine N-methyltransferase KMT2D , and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specifi c, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. SIGNIFICANCE:Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specifi c signaling pathways are activated in tumors. Cancer Discov;6(6);

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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“…Additionally, NF-κB was recently linked to the MYC and MLL epigenetic network (52). Integrin and Syk signaling has also recently been associated with maintaining the undifferentiated program in MLL-AF9 leukemia (67,68). The roles for RNA-binding proteins in myeloid leukemias are less understood.…”

Section: Discussionmentioning

confidence: 99%

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

Park¹,

Gönen²,

Vu³

et al. 2015

J. Clin. Invest.

112

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“…As febrile neutropenia, associated with chemotherapy or HSC transplantation, is a major cause for morbidity and mortality (25), the herein identified role of Del-1 in the induction and maintenance of proper de novo granulopoiesis is important and could be therapeutically exploited in this context. On the other hand, inhibition of the interaction of Del-1 with hematopoietic progenitor cells could be exploited pharmacologically to enhance progenitor mobilization in the context of autologous or allogeneic HSC transplantation or hematologic malignancy (66). The emergence of Del-1 as a critical niche factor that promotes hematopoietic progenitor expansion and retention, as well as myelopoiesis, suggests that this homeostatic factor needs to be seriously considered in the context of BM transplantation or hematological disorders.…”

Section: Cell Cycle Analysis Of Lt-hscs From Edil3mentioning

confidence: 99%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

113

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es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

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In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Cited by 147 publications

References 60 publications

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

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

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

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