Myeloid Malignancies Induced by Alkylating Agents in Nf1 Mice

Mahgoub, Nidal; Taylor, Barry R.; Beau, Michelle M. Le; Gratiot, Mary; Carlson, Katrin M.; Atwater, Susan K.; Jacks, Tyler; Shannon, Kevin

doi:10.1182/blood.v93.11.3617.411a49_3617_3623

Cited by 17 publications

(20 citation statements)

References 31 publications

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“…There is increasing evidence that the development of t-MDS/t-AML is due to a genetic predisposition rather than a drug-dosage effect (47). Children with neurofibromatosis type 1 are at increased risk for therapy-related neoplasms, including myeloid leukemias (48), and neurofibromatosis type 1 mutant mice treated with cyclophosphamide and radiation developed significantly more neoplasms than the wt group (49,50). Interestingly, biochemical investigation of cell lines developed from these malignancies revealed deregulated Ras signaling (50).…”

Section: Discussionmentioning

confidence: 99%

Two Transforming C-RAF Germ-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia

Zebisch¹,

Staber²,

Delavar

et al. 2006

Cancer Research

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Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for (S427G)C-RAF but not for (I448V)C-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a <1/400 frequency of these mutations and, in the case of I448V, inheritance was observed over three generations with another mutation carrier suffering from cancer. Taken together, these data are the first to relate C-RAF mutations to human malignancies. As both mutations are of germ-line origin, they might constitute a novel tumor-predisposing factor.

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Section: Discussionmentioning

confidence: 99%

Two Transforming C-RAF Germ-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia

Zebisch¹,

Staber²,

Delavar

et al. 2006

Cancer Research

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“…Importantly, previous studies have not specifically defined LSC in t-AML/MDS. A number of other investigators have used genetic approaches to model AML and MDS in mice, including NF1, RUNX1, FLT3-ITD, NPM1, and DICER [ 35 – 38 ]. In some cases, these models have been used to describe secondary events leading to AML after treatment of animals with alkylators or radiation [ 35 , 39 – 41 ].…”

Section: Introductionmentioning

confidence: 99%

“…A number of other investigators have used genetic approaches to model AML and MDS in mice, including NF1, RUNX1, FLT3-ITD, NPM1, and DICER [ 35 – 38 ]. In some cases, these models have been used to describe secondary events leading to AML after treatment of animals with alkylators or radiation [ 35 , 39 – 41 ]. However, mouse models relying on transgenic or virally transduced expression of oncogenes might not accurately model clonal mutation accumulation in human t-AML/MDS induced by the nonspecific genetic damage caused by alkylating chemotherapy and radiation therapy.…”

Section: Introductionmentioning

confidence: 99%

Alkylator-Induced and Patient-Derived Xenograft Mouse Models of Therapy-Related Myeloid Neoplasms Model Clinical Disease and Suggest the Presence of Multiple Cell Subpopulations with Leukemia Stem Cell Activity

2016

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Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS. First, we modeled alkylator-induced t-AML/MDS by exposing wild type adult mice to N-ethyl-N-nitrosurea (ENU), resulting in several models of AML and MDS that have clinical and pathologic characteristics consistent with human t-AML/MDS including cytopenia, myelodysplasia, and shortened overall survival. These models were limited by their inability to transplant clinically aggressive disease. Second, we established three patient-derived xenograft models of human t-AML. These models led to rapidly fatal disease in recipient immunodeficient xenografted mice. LSC activity was identified in multiple HSPC subpopulations suggesting there is no canonical LSC immunophenotype in human t-AML. Overall, we report several new t-AML/MDS mouse models that could potentially be used to further define disease pathogenesis and test novel therapeutics.

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“…[41,145 -149] The NF1 patients are also at increased risk for a second malignancy, some of which may be treatment-related. [146,150,151] In different studies, 8% -21% of NF1 patients with a first malignancy developed a second cancer, compared to a frequency of 4% in the general population. [143] Malignancy in NF1 has been reviewed recently.…”

Section: Somatic Alterations In Nf1-associated Mpnstmentioning

confidence: 99%

Clinical and Molecular Consequences of NF1 Microdeletion

Stephens¹

2009

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Myeloid Malignancies Induced by Alkylating Agents in Nf1 Mice

Cited by 17 publications

References 31 publications

Two Transforming C-RAF Germ-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia

Two Transforming C-RAF Germ-Line Mutations Identified in Patients with Therapy-Related Acute Myeloid Leukemia

Alkylator-Induced and Patient-Derived Xenograft Mouse Models of Therapy-Related Myeloid Neoplasms Model Clinical Disease and Suggest the Presence of Multiple Cell Subpopulations with Leukemia Stem Cell Activity

Clinical and Molecular Consequences of NF1 Microdeletion

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