NUP98-fusion transcripts characterize different biological entities within acute myeloid leukemia: a report from the AIEOP-AML group

Bisio, Valeria; Zampini, Matteo; Tregnago, Claudia; Manara, Elena; Salsi, Valentina; Meglio, Annamaria Di; Masetti, Riccardo; Togni, Marco; Giacomo, Dina Di; Minuzzo, Sonia; Leszl, Anna; Zappavigna, Vincenzo; Rondelli, Roberto; Mecucci, Cristina; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina

doi:10.1038/leu.2016.361

Cited by 41 publications

(46 citation statements)

References 15 publications

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“…FLT3 mutations are common in unselected AML patients, and were recently found to occur in 36‐63% of NUP98 ‐rearranged AML . We found Flt3 mutations in the murine AML samples, but not the murine PTCLs.…”

Section: Discussionmentioning

confidence: 47%

“…FLT3 mutations are common in unselected AML patients, and were recently found to occur in 36-63% of NUP98-rearranged AML. 17,20,38 We found Flt3 mutations in the murine AML samples, but not the murine PTCLs. Interestingly, we found several missense mutations and one in-frame deletion in the TKD of Flt3, but no ITD mutations in this sample set.…”

Section: Discussionmentioning

confidence: 63%

“…In addition, mutations in epigenetic modifiers, such as DNMT3A, TET2, ASXL1 and IDH1/2, as well as NPM1, are absent or rare in both human and murine NUP98-fusion AML. 17,19,20,38 An important exception to the above observation is the recurrent Idh1 mutations in NHD13 AML samples (Figure 2, Supporting Information Table S4). IDH genes are recurrently mutated in a wide variety of tumors, including glioblastoma multiforme and AML.…”

Section: Discussionmentioning

confidence: 91%

“…36 In contrast, the most common acquired mutations identified in the murine AML samples involved Ras or tyrosine kinase signaling pathways, similar to findings in human AML in general, 37 as well as NUP98-rearranged AML specifically. 17,19,20,38 We have previously shown that Notch1 PEST domain mutations in murine primary pre-T LBL tumors have a high occurrence at two hot spots; R2361 and S2398. 39 Six of the 14 Notch1 PEST domain mutants identified in this screen mapped to one of those two "hotspots" for mutation.…”

Section: Targeted Resequencing Of Mouse Hematologic Malignancies Idmentioning

confidence: 99%

“…15,16 Although NUP98 fusions have been considered rare events in patients with AML, recent studies show that NUP98 fusions are present in approximately 5% of all pediatric AML patients, and as many as 15% of "normal karyotype" pediatric AML patients. [17][18][19][20] A third murine model of AML that we studied was generated by expression of a CALM-AF10 transgene. 21 CALM-AF10 fusions are associated with AML and immature T-ALL in humans; the AML in both human patients and engineered murine models are characterized by clonal rearrangements of both IG and TCR genes, [22][23][24] suggesting that the cell of origin is multipotent.…”

Section: And Retroviralmentioning

confidence: 99%

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Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Goldberg

Gough

Lee

et al. 2017

Genes Chromosomes & Cancer

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Malignant transformation is a multistep process that is dictated by acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. However, it remains unclear whether the genetic events that occur during transformation are similar in mice and humans. To address that, we chose several transgenic mouse models of hematopoietic malignancies and identified acquired mutations in these mice by means of targeted re-sequencing of known cancer-associated genes as well as whole exome sequencing. We found that mutations that are typically found in acute myeloid leukemia or T cell acute lymphoblastic leukemia patients are also common in mouse models of the respective disease. Moreover, we found that the most frequent mutations found in a mouse model of lymphoma occur in a set of epigenetic modifier genes, implicating this pathway in the generation of lymphoma. These results demonstrate that genetically engineered mouse models (GEMM) mimic the genetic evolution of human cancer and serve as excellent platforms for target discovery and validation.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 91%

Section: Targeted Resequencing Of Mouse Hematologic Malignancies Idmentioning

confidence: 99%

Section: And Retroviralmentioning

confidence: 99%

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Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Goldberg

Gough

Lee

et al. 2017

Genes Chromosomes & Cancer

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CD72 is a pan‐tumor antigen associated to pediatric acute leukemia

Buldini,

Faggin,

Porcù

et al. 2023

Cytometry Pt A

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In the development of novel immunotherapeutic approaches, the step of target identification is a challenging process, because it aims at identifying robust tumor‐associated antigens (TAAs) specific for the pathological population and causing no off‐target effects. Here we propose CD72 as a novel and robust TAA for pediatric acute leukemias. We provided an outline of CD72 expression assessed by flow cytometry on a variety of cancer cell lines and primary samples, including normal bone marrow (BM) samples and hematopoietic stem and progenitor cells. We analyzed CD 72 expression on a cohort of 495 pathological pediatric BM aspirates, including: 215 B‐cell precursor acute lymphoblastic leukemias (BCP‐ALL), 156 acute myeloid leukemias (AMLs), 88 T‐lineage ALLs or lymphoblastic lymphomas with BM infiltration, 13 B‐lineage lymphoblastic lymphomas with BM infiltration, 9 myelodysplastic syndromes with increased blasts (5%–9% blasts on BM: MDS‐IB1) and 14 non‐hematopoietic solid tumors infiltrating BM. Results showed that CD72 is highly expressed in almost all BCP‐ALL and the majority of AML at diagnosis, including BCP‐ALL cases characterized by CD19 loss. These findings support a potential role for advanced diagnostics and novel immunotherapy approaches, providing a pan‐ALL and AML target.

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NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities

Rasouli,

Troester,

Grebien

et al. 2024

HemaSphere

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re‐wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion‐driven AML.

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NUP98-fusion transcripts characterize different biological entities within acute myeloid leukemia: a report from the AIEOP-AML group

Abstract: , NUP98fusion transcripts characterize different biological entities within acute myeloid leukemia: A report from the AIEOP-AML group, Leukemia accepted article preview

Cited by 41 publications

References 15 publications

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

CD72 is a pan‐tumor antigen associated to pediatric acute leukemia

NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities

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