Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice

Gutmann, David H.; Winkeler, Erin L.; Kabbarah, Omar; Hedrick, Nicolé M.; Dudley, Sandra; Goodfellow, Paul J.; Liskay, R. Michael

doi:10.1038/sj.onc.1206768

Cited by 21 publications

(16 citation statements)

References 28 publications

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“…47 Recent studies suggested that defects in DNA repair genes influence NF1 tumor progression in mice and humans, presumably by inactivating normal allele of NF1. 46,48 We found that formation of leukemia with Nf1 biallelic inactivation and Bcl11a overexpression was markedly accelerated, suggesting that other genetic lesions may contribute more significantly to the observed progression of NF1 tumor than loss of heterozygosity of NF1. In addition, myeloproliferative disorder (MPD) can progress to AML; however, there are no solid experimental data explaining the progression of MPD into AML in the context of JMML or other NF1-associated myeloid diseases.…”

Section: Discussionmentioning

confidence: 86%

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A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

Yin

Delwel

Valk

et al. 2009

Blood

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NF1 inactivation occurs in specific human cancers, including juvenile myelomonocytic leukemia, an aggressive myeloproliferative disorder of childhood. However, evidence suggests that Nf1 loss alone does not cause leukemia. We therefore hypothesized that inactivation of the Nf1 tumor suppressor gene requires cooperating mutations to cause acute leukemia. To search for candidate genes that cooperate with Nf1 deficiency in leukemogenesis, we performed a forward genetic screen using retroviral insertion mutagenesis in Nf1 mutant mice. We identified 43 common proviral insertion sites that contain candidate genes involved in leukemogenesis. One of these genes, Bcl11a, confers a growth advantage in cultured Nf1 mutant hematopoietic cells and causes early onset of leukemia of either myeloid or lymphoid lineage in mice when expressed in Nf1-deficient bone marrow. Bcl11a-expressing cells display compromised p21 Cip1 induction, suggesting that Bcl11a's oncogenic effects are mediated, in part, through suppression of p21 Cip1 .Importantly, Bcl11a is expressed in human chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia samples. A subset of AML patients, who had poor outcomes, of 16 clusters, displayed high levels of BCL11A in leukemic cells. These findings suggest that deregulated Bcl11a cooperates with Nf1 in leukemogenesis, and a therapeutic strategy targeting the BCL11A pathway may prove beneficial in the treatment of leukemia.

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Section: Discussionmentioning

confidence: 86%

“…Although the cooperation of Nf1 deficiency with other genetic alterations has been proposed or attempted, 29,45,46 convincing evidence is still lacking. Our results suggest the existence of a strong synergetic effect of Bcl11a up-regulation and Nf1 deficiency.…”

Section: Discussionmentioning

confidence: 99%

A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

Yin

Delwel

Valk

et al. 2009

Blood

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“…Furthermore, no LOH has been observed in all leukemias developing in an Nf1-haploinsufficient tumor model crossed into mice with a defect in the DNA mismatch repair enzyme Mlh1. 43 Conditional deletion of a floxed Nf1 allele in Icsbp Ϫ/Ϫ Nf1 f1/Ϫ should allow to mimic LOH and to study the consequences of the complete loss of Nf1 for the development of leukemias in mice.…”

Section: Progression Of Leukemiasmentioning

confidence: 99%

Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias

Koenigsmann

Rudolph

Sander

et al. 2009

Blood

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“…The specificity of the primary antibodies, eNOS and iNOS, has been tested on mouse brain extract and LPS/IFN-g-stimulated macrophage (RAW 264.7), respectively, with Western blotting. Both antibodies have been widely applied for the NOS research (3,4,6,7,10,11,21,26,32).…”

Section: Animals and Groupsmentioning

confidence: 99%

Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury

Wang

Li²,

Weisel³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Decreased levels of tetrahydrobiopterin (BH4), an absolute cofactor for nitric oxide synthase (NOS), lead to uncoupling of NOS into a superoxide v. nitric oxide producing enzyme, and it is this uncoupling that links it to the development of vascular disease. However, the effects of in vivo deficiency of BH4 on neointimal formation after vascular injury have not been previously investigated. Hph-1 mice, which display 90% deficiency in guanine triphosphate cyclohydrolase I, the rate limiting enzyme in BH4 synthesis, were used. Hph-1 and wild-type mice, treated with either vehicle or BH4 (n ϭ 15 per group), were subjected to wire-induced femoral artery injury, and NOS expression and activity, inflammation, cell proliferation, superoxide production, and neointimal formation were assessed. The major form of NOS expressed over vessel wall after vascular injury was endothelial NOS. Hph-1 mice exhibited lower NOS activity (2.8 Ϯ 0.3 vs. 4.5 Ϯ 0.4 pmol/min/mg protein, P Ͻ 0.01), and higher aortic superoxide content (5.2 Ϯ 2.0 ϫ 10 5 cpm vs. 1.6 Ϯ 0.7 ϫ 10 5 cpm, P Ͻ 0.01) compared with wild-type controls, indicating uncoupling of NOS. Treatment of hph-1 mice with BH4 significantly increased NOS activity (from 2.8 Ϯ 0.3 to 4.1 Ϯ 0.4 pmol⅐min Ϫ1 ⅐mg protein Ϫ1, P Ͻ 0.05), and attenuated superoxide production (from 5.2 Ϯ 2.0 ϫ 10 5 cpm to 0.8 Ϯ 0.7 ϫ 10 5 cpm, P Ͻ 0.05). Hph-1 mice also had higher inflammatory reactions and more cell proliferation after vascular injury. Furthermore, hph-1 mice responded by a marked increase in neointimal formation at 4 wk after vascular injury, compared with wild-type controls (intima:media ratio: 4.5 Ϯ 0.5 vs. wild-type 0.7 Ϯ 0.1, P Ͻ 0.001). Treatment of hph-1 mice with BH4 prevented vascular injury-induced increase in neointimal formation (intima:media ratio: 1.4 Ϯ 0.1 vs. hph-1, P Ͻ 0.001). Treatment had no effect on wild-type controls. In summary, we describe, for the first time, that in vivo BH4 deficiency facilitates neointimal formation after vascular injury. Modulation of BH4 bioavailability is an important therapeutic target for restenosis. restenosis; superoxide; nitric oxide synthase NEOINTIMAL FORMATION AND RESTENOSIS after vascular injury have been ascribed to a number of factors, including endothelial dysfunction, increased reactive oxygen species production, and accelerated smooth muscle cell migration and proliferation (5, 23). Nitric oxide (NO) produced by endothelium plays an important role in attenuating smooth muscle migration and proliferation, and decreasing neointimal hyperplasia by numerous mechanisms (25, 28). Tetrahydrobiopterin (BH4) is an absolute cofactor required for nitric oxide synthase (NOS) and maintains NOS as a NO vs. superoxide-producing enzyme (18). BH4 exerts this action through serving as an electron donor for the hydroxylation of L-arginine. Suboptimal concentrations of BH4, as observed in states of cardiovascular disease, led to an uncoupling of NOS with diminished NO and exaggerated superoxide anion production. NOS may become a source of oxygen-de...

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Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice

Cited by 21 publications

References 28 publications

A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias

Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury

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