v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation

Kahn, Patricia; Frykberg, Lars; Brady, Claire; Stanley, Irene J.; Beug, Hartmut; Vennström, Björn; Graf, Thomas

doi:10.1016/0092-8674(86)90320-x

Cited by 147 publications

(55 citation statements)

References 46 publications

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“…Examples include AML͞ETO or NUP98͞HOXA9 translocations in combination with TEL͞PDGF␤R or BCR͞ABL, respectively (29,30). Avian model systems also have demonstrated mutations in both cell surface receptors and nuclear factors in leukemia development (31,32). In addition, although activated kinases and altered function of hematopoietic transcription factors are associated with leukemia (33), neither mutation alone is sufficient to induce AML in mouse BMT models (24,34,35).…”

Section: Discussionmentioning

confidence: 99%

PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model

Kelly

Kutok

Williams

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

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Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor ␣ (RAR␣). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RAR␣ in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML͞ RAR␣ from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML͞RAR␣ can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML͞RAR␣ transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML͞RAR␣ transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML͞RAR␣ and FLT3-ITD in development of the murine APL phenotype.A cute promyelocytic leukemia (APL) comprises 5-10% of cases of AML and is almost always associated with rearrangement of the retinoic acid receptor ␣ (RAR␣) gene as a consequence of balanced reciprocal chromosomal translocations. The t(15;17)(q22;q11.2) is the most common such translocation and most APL cells with this translocation express both the promyelocytic leukemia (PML)͞RAR␣ and RAR␣͞PML fusion proteins. Mouse models and cell culture assays have demonstrated that the PML͞RAR␣ fusion protein contributes to the leukemic phenotype in part by inhibiting differentiation and promoting survival of hematopoietic progenitor cells (1-6).Data from murine models and analysis of human APL genotypes indicate that the PML͞RAR␣ fusion protein is necessary, but not sufficient for the APL disease phenotype. Transgenic mice expressing PML͞RAR␣ under the control of the cathepsin G promoter can develop acute myeloid leukemia (AML) with many of the features of APL (1, 2, 7, 8). All transgenic animals expressing this transgene display a myeloproliferative syndrome characterized by elevated numbers of myeloid cells in the marrow and spleen. After a latency of 6-13 months, 15-20% of animals develop an APL-like disease. However, the penetrance increases to about 60% when both the PML͞RAR␣ and the reciprocal RAR␣͞PML cDNAs are expressed in early myeloid cel...

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Section: Discussionmentioning

confidence: 99%

PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model

Kelly

Kutok

Williams

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

View full text Add to dashboard Cite

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“…We then asked whether a constitutive activation of this MEK-1 pathway might impair the differentiation process, similarly to what has previously been shown for Ras ectopic expression (Kahn et al, 1986). For this, T2ECs were infected with a retroviral vector expressing MEK-1DD, a constitutively active form of MEK-1 Pages et al, 1994).…”

Section: Constitutive Mek-1 Activation Inhibits T2ecs Differentiationmentioning

confidence: 99%

The MEK-1/ERKs signalling pathway is differentially involved in the self-renewal of early and late avian erythroid progenitor cells

et al. 2003

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“…and the five following p-ras exons, providing a strong promoter for efficient transcription of p21ras mRNAs and the packaging signal (10,(28)(29)(30)(31). After addition of the 3' LTR via DNA (31) or RNA (32) recombination, a replicating progenitor virus formed that can induce malignant transformation.…”

Section: Resultsmentioning

confidence: 99%

Development of transforming function during transduction of proto-ras into Harvey sarcoma virus.

Läng¹,

Treinies²,

Duesberg³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic retroviruses are generated by transduction of the coding region of a protooncogene and acquire genetic changes during subsequent replication. Critical genetic events which occurred during and after transduction of rat proto-ras-lHa into Harvey sarcoma virus were identified by evaluating the transforming activity of plausible synthetic progenitor proviruses encompassing the complete proto-ras genomic region with or without various 5' deletions. All progenitor proviruses induced phenotypic transformation of mouse NIH 3T3 cells, although with a 5-to 10-fold lower frequency than Harvey sarcoma provirus. Although no tumor formation was observed in vivo after inoculation in the absence of helper murine retrovirus, both wild-type and progenitor viruses inoculated in the presence of helper virus induced tumors in newborn BALB/c mice. No critical alterations of the p2l1 coding region and no deletion of 5' genomic elements were detected in a progenitor virus encompassing the complete proto-ras genomic region that had been isolated from tumors. However, one progenitor virus that included all proto-ras exons induced tumors with a decreased latency. This virus contained a mutation in codon 12 (glycine to valine), which had apparently been selected during tumorigenesis in vivo. During the genesis of Harvey sarcoma virus, critical steps conferring transforming function are therefore transduction of coding proto-ras exons and enhancement of their transforming function by specific amino acid changes in p2lrs.Balb sarcoma virus (BalbSV) and Harvey sarcoma virus (HaSV) induce erythroblastosis and fibrosarcomas in infected mice by an apparent single-step mechanism (1-3). The two viruses express oncogenic p2lras proteins mutated in amino acid 12 and amino acids 12 and 59, respectively, relative to the normal p2lras protein of rat proto-ras-lHa (p-ras_JHa). Previous studies showed that the transforming function of both viruses was enhanced but did not depend on the virus-specific codons described (4-10). The latency of malignant tumor induction in infected mice and the efficiency of phenotypic transformation in vitro were comparable for viral ras (v-ras)-and p-ras-expressing viruses in one study (5). In contrast, Velu et al. (7) reported a correlation between the lower frequency of focal transformation of mouse NIH 3T3 cells by p-ras-expressing viruses and the preferential induction of lymphoid versus erythroblastic tumors in vivo. Sequence comparison between genomic rat p-ras-l sequences and v-ras of HaSV revealed the presence of one noncoding exon (exon 1) and a putative second noncoding exon (exon ?) upstream of the v-ras coding region (4, 6). Putative p-ras promoter regions and both noncoding exons are part of a 3.6-kbp HindIII (-2600)-HindIII (1026) rat genomic DNA fragment (Fig. 1) MATERIALS AND METHODSConstruction of Progenitor Proviruses. The construction of wild-type HaS provirus (termed pA) and synthetic HaS proviruses pApraslX and pA6.2-pras was described previously (4-6). pA6.2-pras (Fig.

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v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation

Cited by 147 publications

References 46 publications

PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model

PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model

The MEK-1/ERKs signalling pathway is differentially involved in the self-renewal of early and late avian erythroid progenitor cells

Development of transforming function during transduction of proto-ras into Harvey sarcoma virus.

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