Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Carratt, Sarah A.; Braun, Theodore P.; Coblentz, Cody; Schonrock, Zachary; Callahan, Rowan; Curtiss, Brittany M.; Maloney, Lauren; Foley, Amy; Maxson, Julia E.

doi:10.1038/s41375-021-01278-2

Cited by 17 publications

(19 citation statements)

References 16 publications

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“…For these studies, we utilized V5-tagged- SETBP1 constructs with codon-optimization, described previously 12 . SETBP1 constructs were cloned into pMSCV-IRES-mCherry (a gift from Dario Vignali; Addgene plasmid # 52114; http://n2t.net/addgene:52114; RRID:Addgene_52114) or the Retro-X™ Tet-One™ Inducible Expression System (Puro) (TakaRa Bio USA, Cat #634307).…”

Section: Methodsmentioning

confidence: 99%

“…As previously described 12 , CSF3R T618I + SETBP1 Wt and CSF3R T618I + SETBP1 D868N murine cell lines were initially derived from mouse bone marrow cells that were harvested from CFU assays (Figure 1A-D). Subsequent cell lines, including the doxycycline-inducible cell line in Figure 3 ( CSF3R T618I +SETBP1 D868N -dox cell line) were generated by sorting transduced murine bone marrow directly into IMDM with 20% FBS, without cytokine support.…”

Section: Methodsmentioning

confidence: 99%

“…In a human embryonic kidney model (Flp-In™-293), SETBP1 was shown to recruit the MLL1 transcriptional activator complex and directly upregulate MECOM and MECOM target genes 8 . Recently, we found that SETBP1 can modulate disease biology driven by co-occurring mutations 12 . Specifically, in the context of Ras-pathway driven leukemia, mutant SETBP1 can increase MAPK pathway activation 12 .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we found that SETBP1 can modulate disease biology driven by co-occurring mutations 12 . Specifically, in the context of Ras-pathway driven leukemia, mutant SETBP1 can increase MAPK pathway activation 12 . The goal of this study was to understand the context specific role of SETBP1 mutations in CNL to enable the development of therapeutic approaches that improve treatment outcomes for these patients.…”

Section: Introductionmentioning

confidence: 99%

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Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Carratt

Kong

Curtiss

et al. 2021

Preprint

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Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs—most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by epigenetic modulatory drugs. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.Statement of SignificanceSETBP1 is frequently mutated in chronic neutrophilic leukemia, but its role in the biology of this disease is unclear. We find that mutant SETBP1 enhances transcription of Myc and Myc target genes to promote aggressive disease biology, and that these oncogenic transcriptional programs can be reversed by epigenetic modulatory drugs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Carratt

Kong

Curtiss

et al. 2021

Preprint

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“…In JMML, SETBP1 mutations associate with PTPN11 or NRAS somatic mutations [ 74 ]. Interestingly, a recently published mouse model combining SETBP1 and NRAS mutations has shed some light on the mechanism of interaction between these two factors by showing that the aberrant expression of SETBP1 enhances both NRAS gene expression signature and NRAS-driven MAPK protein phosphorylation [ 81 ].…”

Section: Genetic Alterations In Jmmlmentioning

confidence: 99%

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Fiñana

Gómez-Molina

Alonso-Moreno

et al. 2022

Cancers

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Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.

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Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer

Zhang

Yang

et al. 2023

Molecular Oncology

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A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer (GC). We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II–III GC. Seventy‐nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2‐lymphadenectomy. Plasma at baseline, post‐NACT, and after surgery, and tissue at pretreatment and surgery were collected. We used a 425‐gene panel to detect genomic alterations (GAs). Results show that the mean cell‐free DNA concentration of patients with clinical stage III was significantly higher than patients with stage II (15.43 ng·mL−1 vs 14.40 ng·mL−1). After receiving NACT and surgery, the overall detection rate of ctDNA gradually reduced (59.5%, 50.8%, and 47.4% for baseline, post‐NACT, and postsurgery). The maximum variant allele frequency (max‐VAF) and the number of GAs decreased from 0.50% to 0.08% and from 2.9 to 1.7 after NACT. For patients with a partial response after NACT, the max‐VAF and the number of GAs declined significantly, but they increased for patients with progressive disease. Patients with detectable ctDNA at baseline, after NACT, or after surgery have a worse overall survival (OS) than patients with undetectable ctDNA. The estimated 3‐year OS was 73% for the post‐NACT ctDNA‐negative patients and 34% for ctDNA‐positive. Patients with perpetual negative ctDNA before and after NACT have the best prognosis. In conclusion, ctDNA was proposed as a potential biomarker to predict prognosis and monitor the NACT response for stage II–III GC patients.

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Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Cited by 17 publications

References 16 publications

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer

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