Genetic Pathways Leading to Therapy-Related Myeloid Neoplasms

Stoddart, Angela; McNerney, Megan E.; Bartom, Elizabeth T.; Bergerson, Rachel J.; Young, David J.; Qian, Zhijian; Wang, Jianghong; Fernald, Anthony A.; Davis, Elizabeth M.; Larson, Richard A.; White, Kevin P.; Beau, Michelle M. Le

doi:10.4084/mjhid.2011.019

Cited by 13 publications

(27 citation statements)

References 50 publications

(83 reference statements)

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“…Using molecular mapping approaches, 2 minimally deleted regions have been identified: 5q31.2 in t-MN and MDS/AML, and 5q33.1 in MDS with an isolated del(5q). 1,5,6 Current studies support a haploinsufficiency model, in which loss of a single allele of more than one gene on 5q cooperate in the development of myeloid neoplasms. In fact, a number of genes and several micro RNA sequences located on 5q, including APC, EGR1, CTNNA1, DIAPH1, HNRNPA0, HSPA9, RPS14, and miR-145/146a, have been implicated in the development of myeloid disorders due to a gene dosage effect.…”

Section: Introductionmentioning

confidence: 89%

“…1 The incidence of t-MN is rising commensurate with improvements in cancer treatments and increased survival. The prognosis for these patients has not improved substantially in several decades (median survival, 8 months); thus, t-MN is an increasingly challenging clinical problem.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, a number of genes and several micro RNA sequences located on 5q, including APC, EGR1, CTNNA1, DIAPH1, HNRNPA0, HSPA9, RPS14, and miR-145/146a, have been implicated in the development of myeloid disorders due to a gene dosage effect. 1,7,8 For example, RPS14 and miR-145/146a cooperate in the pathogenesis of MDS with an isolated del(5q). 6 We previously demonstrated that EGR1 (5q31.2), which is deleted in all t-MN patients with a del(5q) and APC (5q22) and is deleted in .95% of patients, are both expressed at haploinsufficient levels, and inactivating mutations have not been identified in the remaining alleles, 9,10 confirming that these genes are not acting as typical tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

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Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc

Stoddart¹,

Wang²,

Fernald³

et al. 2014

Blood

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Key Points• Haploinsufficiency of Egr1, Apc, and Tp53 in mice cooperate to model the pathogenesis of the early stages of t-MN with a del(5q).• Exposure of an Apc haploinsufficient BM microenvironment to radiation and/or an alkylating agent accelerates disease development.Therapy-related myeloid neoplasms (t-MN) are a late complication of the successful use of cytotoxic therapy for patients with cancer. A heterozygous deletions of the long arm of chromosome 5 [del(5q)], observed in 40% of patients, is associated with prior exposure to alkylating agents, and a high frequency of TP53 loss or mutation. In previous studies, we demonstrated that haploinsufficiency of 2 del(5q) genes, Egr1, and Apc, individually play a role in the pathogenesis of hematologic disease in mice. We now show that loss of one copy of Egr1 or Tp53 in an Apc haploinsufficient background (Apc) accelerated the development of a macrocytic anemia with monocytosis, early features of t-MN. The development of anemia was significantly accelerated by treatment of mice with the alkylating agent, N-ethyl-N-nitrosourea (ENU), regardless of the levels of expression of Egr1 and Tp53. Transplantation of either wild type; Egr1 -induced anemia was cell extrinsic and potentiated by ENU mutagenesis. These data emphasize the synergistic role of cell intrinsic and cell extrinsic (microenvironment) factors in the pathogenesis of t-MN, and raise awareness of the deleterious effects of cytotoxic therapy on the stromal microenvironment. (Blood. 2014;123(2):228-238)

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc

Stoddart¹,

Wang²,

Fernald³

et al. 2014

Blood

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“…A deletion of the long arm of chromosome 5, del(5q), or loss or deletion of chromosome 7, is frequently noted in bone marrow (BM) cells of patients with t-MN after alkylating agent therapy, implicating loss of function of tumor suppressor genes in the pathogenesis of this disease. [1][2][3] The identification of the involved gene(s) on chromosome 5 has been challenging, in large part because the deletions are extensive, on the order of $70 Mb, and homozygous deletions have not been identified. 4,5 However, a number of genes and several micro RNAs (miRNAs) located on 5q, including RPS14, miRNA-145, miRNA-146a, early growth response 1 gene (EGR1), the adenomatous polyposis coli gene (APC), CTNNA1, HSPA9, and DIAPH1, have been implicated in the development of myeloid disorders caused by a gene dosage effect.…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice

Stoddart¹,

Fernald²,

Wang³

et al. 2014

Blood

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• Egr1 haploinsufficiency in cooperation with reduced Tp53 activity accelerates the development of hematologic disease in mice.• Loss of 1 copy of Egr1 and Apc in hematopoietic stem cells, in cooperation with Tp53 loss, results in myeloid neoplasms.An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML. (Blood. 2014;123(7):1069-1078)

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“…Rather, current studies support a haploinsufficiency model, in which loss of a single allele of more than one gene on 5q contributes to the pathogenesis of t-MN. 33 The current challenge is identifying which of the numerous genes in the deleted chromosome 5 segment are involved in the pathogenesis of human t-MN. In this paper, we show that decreased HNRNPA0 expression is characteristic of leukemias with a del(5q), and that recapitulating loss of Hnrnpa0 expression in mouse hematopoietic cells alters myeloid differentiation.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nhave a profound impact upon hematopoiesis, and consequently contribute to the changes seen in t-MN patients.In this study, we now add HNRNPA0 to the growing list of AUBPs that are recognized for their vital roles in hematopoiesis and leukemogenesis. Herein, we show that HNRNPA0 is highly expressed in hematopoietic stem cells, and its expression exhibits dynamic changes during the course of differentiation. Deletion of a single allele of HNRNPA0 is associated with haploinsufficient transcript levels in CD34 + cells from t-MN patients with a del(5q). Modeling HNRNPA0 haploinsufficiency in mouse cells alters myeloid lineage fate, in part through changes in the expression of ARE-containing genes, suggesting that a decreased dose of HNRNPA0 in t-MN patients may contribute to leukemogenesis. Moreover, we determined that ARE mRNAs in t-MN patients with a del(5q) are enriched in transcripts that encode proteins associated with increased growth and proliferation. Methods Retroviral transduction and in vitro differentiation of PUER and primary mouse hematopoietic cellsA short interfering RNA hairpin (shRNA), designed to match bases 288 to 306 of the open reading frame of Hnrnpa0 with a 9 nucleotide loop in the center, or a scrambled, irrelevant sequence, 17 was cloned into pBanshee-GFP (an MSCV-based construct with P CMV -driven GFP). The PUER cell line or mouse bone marrow cells from BALB/cAnNTac mice (Taconic, Hudson, NY, USA) were transduced by spinoculation with viral supernatants from HEK-293T cells co-transfected with the shRNA-containing pBanshee and pCL-ECO packaging plasmids (Imgenex, San Diego, CA, USA) using Effectene (Qiagen, Germantown, MD, USA). Two days post infection, the cells were sorted on a FACSAria (BD Biosciences, San Jose, CA, USA) for GFP positivity. All animal studies were approved by the University of Chicago Institutional Animal Care and Use Committee and mice were housed in a fully-AALAC-accredited facility. GFP + sorted PUER cells, expressing the Hnrnpa0 or control shRNA, were expanded in IL-3 for four days and then treated with 1-5 nM 4-hydroxytamoxifen (4-OHT, >98% (TLC) Z-isomer, Sigma, St. Louis, MO, USA) to induce macrophage differentiation. For gene expression, flow cytometry and morphological analyses, cells were sampled at 24 h, 4 days, and 7days, respectively. GFP + bone marrow cells were plated in MethoCult GF M3434 (StemCell Technologies, Vancouver, BC, Canada). After 12 days of incubation, colonies of greater than 50 cells were scored for morphology by inverted light microscopy. Cells were then collected and stained with Mac-1 (CD11b) antibodies in combination with either F4/80 or Gr-1 (Ly-6G) antibodies, and analyzed on a FASCanto benchtop flow cytometric analyzer (BD Biosciences, San Jose, CA, USA). Patient samplesAll 38 t-MNs used for gene expression profiling analysis were obtained from patients treated with chemotherapy and/or radiation therapy at the University of Chicago who were diagnosed with t-MN between January 1984...

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Genetic Pathways Leading to Therapy-Related Myeloid Neoplasms

Cited by 13 publications

References 50 publications

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc

Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

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