Bethesda proposals for classification of nonlymphoid hematopoietic  neoplasms in mice

Kogan, Scott C.; Ward, Jerrold M.; Anver, Miriam R.; Berman, Jules J.; Brayton, Cory; Cardiff, Robert D.; Carter, John S.; Coronado, Sherri de; Downing, James R.; Fredrickson, T. N.; Haines, Diana C.; Harris, Alan W.; Harris, Nancy L.; Hayashi, Hiroshi; Jaffe, Elaine S.; MacLennan, Ian C. M.; Pandolfi, Pier Paolo; Pattengale, Paul K.; Perkins, Archibald S.; Simpson, R. Mark; Tuttle, Mark S.; Wong, Joanne; Morse, Herbert C.

doi:10.1182/blood.v100.1.238

Cited by 391 publications

(325 citation statements)

References 9 publications

(11 reference statements)

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“…Interestingly, several mice (n ϭ 5) had BM cells that were more than 90% for B220; however, these cells exhibited a lower fluorescent intensity than control B220 ϩ cells, suggesting they are of a different population, and we thus describe them as B220 lo . Many of the NUP98-TOP1 PB, BM, and spleen cells were morphologically "immature forms/blasts," consistent with the diagnosis of a myeloid leukemia 51 (Figure 5B). The BM from NUP98-TOP1 mice showed greatly increased numbers of both induces monoclonal or oligoclonal disease, which is transplantable to secondary recipients.…”

Section: Nup98-top1 Induces a Lethal Myeloid Leukemiasupporting

confidence: 53%

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

Gurevich

Aplan

Humphries

2004

Blood

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Chromosomal rearrangements of the 11p15 locus have been identified in hematopoietic malignancies, resulting in translocations involving the N-terminal portion of the nucleoporin gene NUP98. Fifteen different fusion partner genes have been identified for NUP98, and more than one half of these are homeobox transcription factors. By contrast, the NUP98 fusion partner in t(11;20) is Topoisomerase I (TOP1), a catalytic enzyme recognized for its key role in relaxing supercoiled DNA. We now show that retrovirally engineered expression of NUP98-TOP1 in murine bone marrow confers a potent in vitro growth advantage and a block in differentiation in hematopoietic precursors, evidenced by a competitive growth advantage in liquid culture, increased replating efficient of colony-forming cells (CFCs), and a marked increase in spleen colonyforming cell output. Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly, and mild anemia. Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity essentially left unaltered the growth-promoting and leukemogenic effects of NUP98-TOP1. These findings, together with similar biologic effects reported for NUP98-HOX fusions, suggest unexpected, overlapping functions of NUP98 fusion genes, perhaps related to common DNA binding properties. IntroductionA heterogenous group of hematopoietic malignancies has been described that are characterized by chromosomal translocations that create fusion genes involving the N-terminal portion of the nucleoporin gene, NUP98, on chromosome 11p15. 1 To date, 15 distinct fusion partners have been identified in NUP98 translocations. The most frequently observed fusion partners for NUP98 belong to the homeobox family of transcription factors and include HOXA9, 2,3 HOXD13, 4 HOXD11, 5 HOXA11, 6 HOXA13, 7,8 HOXC11,9 and HOXC13 10 as well as the nonclustered homeobox gene PMX1. 11 Recent studies in murine model systems have clearly demonstrated that both NUP98-HOXA9 and NUP98-HOXD13 play a causal and overt role in the pathogenesis of leukemia. 12,13 Furthermore, the disease onset can be greatly accelerated in these models by coexpression of the NUP98-HOX fusion gene and the HOX co-factor Meis1. These reports are consistent with the observations that HOX genes play key roles in the regulation of hematopoiesis and that overexpression of select HOX genes (eg, HOXA10, 14 HOXB3 15 ) lead to leukemia.In addition to the HOX genes, 7 "variant" partner genes that are associated with a wide range of biologic functions have been identified in fusion with NUP98 in hematopoietic malignancies. These include DDX10, 16,17 RAP1GDS1,18,19 Topoisomerase I, 20 LEDGF, 21 NSD1, 22 NSD3, 23 and Adducin 3. 24 These NUP98 fusion partner genes are diverse in function and, in contrast to the HOX fusion partners, are not known to have a specific or unique function in hematopoiesis.An intriguing example of one such non-HOX partner is Topoisomerase I (...

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Section: Nup98-top1 Induces a Lethal Myeloid Leukemiasupporting

confidence: 53%

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

Gurevich

Aplan

Humphries

2004

Blood

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“…As seen before for the Mll; Enl; Lmo2-Cre mice , post-mortem examination of these leukaemic groups (Lmo2-, Rag1-and Lck-Cre translocators) revealed a myeloid lineage malignancy typified by splenomegaly, swollen lymph nodes and pale liver. By the Bethesda classification of non-lymphoid tumours (Kogan et al, 2002), these mice developed a myeloproliferative-like myeloid leukaemia. The Mll; Enl; Lck-Cre translocator group showed a relative long lag before the appearance of leukaemia.…”

Section: Resultsmentioning

confidence: 99%

Leukaemia lineage specification caused by cell-specific Mll-Enl translocations

et al. 2007

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Chromosomal translocations involving the Mixed-Lineage Leukaemia (MLL) gene underlie many human leukaemias and MLL rearrangements are found in both acute myelogenous and acute lymphoblastic leukaemias. To assess the functionally relevant haematopoietic cell contexts for MLL fusions to be tumorigenic, we have generated different lines of mice in which de novo Mll-associated translocations occur. In these models, reciprocal chromosomal translocations occur by means of Cre-loxPmediated recombination (translocator mice) in different cells of the haematopoietic system (namely haematopoietic stem cells, semi-committed progenitors or committed T or B cells). Translocations between Mll and Enl cause myeloid neoplasias, initiating in stem cells or progenitors while no tumours arose when the translocation was restricted to the B-cell compartment. Despite the absence of tumorigenesis, Mll-Enl translocations did occur and Mll-Enl fusion mRNA was expressed in B-cell-restricted translocators. A permissive cellular environment is therefore required for oncogenicity of Mll-associated translocations since the occurrence of Mll-Enl does not promote unrestricted proliferation in all haematopoietic cellular contexts, consistent with a specific instructive role of the MLL-fusion proteins in leukaemogenesis.

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“…Cell suspensions were prepared from lymphoma samples for FACS analysis and characterized using T-cell, B-cell and myeloid surface markers. 34,35 MEFs and primary thymocyte treatments. MEFs were isolated from 12.5-day-old pups.…”

Section: Methodsmentioning

confidence: 99%

Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis

et al. 2013

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Mutant p53 proteins not only lose their tumor-suppressor function but some acquire oncogenic gain of function (GOF). The published mutp53 knock-in (KI) alleles (R172H, R270H, R248W) manifest GOF by broader tumor spectrum and more metastasis compared with the p53-null allele, but do not shorten survival. However, whether GOF also occurs with other mutations and whether they are all biologically equal is unknown. To answer this, we created novel humanized mutp53 KI mice harboring the hot spot alleles R248Q and G245S. Intriguingly, their impact was very different. Compared with p53-null mice, R248Q/ À mice had accelerated onset of all tumor types and shorter survival, thus unprecedented strong GOF. In contrast, G245S/ À mice were similar to null mice in tumor latency and survival. This was associated with a twofold higher T-lymphoma proliferation in R248Q/ À mice compared with G245S/ À and null mice. Moreover, R248Q/ À hematopoietic and mesenchymal stem cells were expanded relative to G245S/ À and null mice, the first indication that GOF also acts by perturbing pretumorous progenitor pools. Importantly, these models closely mirror Li-Fraumeni patients who show higher tumor numbers, accelerated onset and shorter tumor-free survival by 10.5 years when harboring codon R248Q mutations as compared with Li-Fraumeni patients with codon G245S mutations or p53 deletions/loss. Conversely, both KI alleles caused a modest broadening of tumor spectrum with enhanced Akt signaling compared with null mice. These models are the first in vivo proof for differential oncogenic strength among p53 GOF alleles, with genotype-phenotype correlations borne out in humans. p53 is mutated in over 50% of human cancers. 1 In response to oncogenic mutations or DNA damage, wtp53 rapidly stabilizes in the nucleus, triggering a transcriptional program of cell cycle arrest, DNA repair, senescence, autophagy and apoptosis. The vast majority (95%) of p53 mutations in human cancer are missense mutations (mutp53). They are broadly distributed within the DNA-binding domain (aa 102-292) with 6 hot spots at codons 175, 245, 248, 249, 273 and 282, and generate conformationally aberrant proteins with impaired or abrogated transcriptional function and abrogated proapoptotic mitochondrial actions. 1,2 Accumulating evidence indicates multiple newly acquired active roles for mutp53 proteins in promoting tumorigenesis. [3][4][5] Knock-in (KI) mouse models expressing the hot spot mutant alleles R172H and R270H (equivalent to human R175H and R273H) from the endogenous promoter provided definitive proof that at least certain p53 mutants exhibit gain of functions (GOFs). 6,7 They established that these mutp53 proteins cause a broader tumor spectrum including carcinomas and progression of certain tumor types to a more invasive and metastatic phenotype compared with tumors of p53 À / À or p53 þ / À mice. Similarly, three HUPKI (Humanized p53 Knock In) mouse models (harboring R175H, R273H and R248W) show broader tumor spectrum compared with null mice, confirming a GOF fo...

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Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice

Cited by 391 publications

References 9 publications

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation

Leukaemia lineage specification caused by cell-specific Mll-Enl translocations

Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis

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