FLT3-ITD Knockin Impairs Hematopoietic Stem Cell Quiescence/Homeostasis, Leading to Myeloproliferative Neoplasm

The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.

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“…7 C). A similar phenotype has been described previously in an Flt3-ITD animal model (Chu et al, 2012).…”

Section: Generation Of In Vivo Loss Of Function Cohesin Animal Modelssupporting

confidence: 78%

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Mullenders¹,

Aranda-Orgillés²,

Lhoumaud³

et al. 2015

J Cell Biol

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“…Another report has shown that introduction of an IDH2 mutant into FLT3-ITD knockin hematopoietic progenitor cells induced AML (19). Because FLT3-ITD knockin mice develop chronic myelomonocytic leukemia (42,43), mutations have accumulated in FLT3-ITD knockin mice that effectively predispose them to develop AML by introducing the IDH2 mutations. Another report has shown that a xenograft model of IDH2-mutant cells was predisposed to develop sarcomas (20).…”

Section: Discussionmentioning

confidence: 99%

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Ogawara¹,

Katsumoto²,

Aikawa³

et al. 2015

Cancer Research

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IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert a-ketoglutarate (a-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of a-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM) þ/À hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc þ cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy.

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“…We chose mouse models incorporating two common class I mutations observed in human AML: FLT3-ITD (Nakao et al 1996) and Nras G12D (Schubbert et al 2007). Flt3-ITD knock-in mice develop a chronic myelomonocytic leukemia that never progresses to AML (Lee et al 2007;Chu et al 2012), whereas Mx-1-mediated activation of a latent ''lox-stop-lox'' Nras G12D allele (Haigis et al 2008) in hematopoietic cells results in a myeloproliferative disorder Wang et al 2011). …”

Section: Idh2 Mutants Cooperate With Flt3-itd or Nrasg12d To Promote mentioning

confidence: 99%

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

et al. 2013

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Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.

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FLT3-ITD Knockin Impairs Hematopoietic Stem Cell Quiescence/Homeostasis, Leading to Myeloproliferative Neoplasm

Cited by 83 publications

References 68 publications

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

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