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Article ; Online: Discovery of U2AF1 neoantigens in myeloid neoplasms.

Biernacki, Melinda Ann / Lok, Jessica / Black, Ralph Graeme / Foster, Kimberly A / Cummings, Carrie / Woodward, Kyle B / Monahan, Tim / Oehler, Vivian G / Stirewalt, Derek L / Wu, David / Rongvaux, Anthony / Deeg, Hans Joachim / Bleakley, Marie

Journal for immunotherapy of cancer

2023 Volume 11, Issue 12

Abstract: Background: Myelodysplastic syndromes (MDS) arise from somatic mutations acquired in hematopoietic stem and progenitor cells, causing cytopenias and predisposing to transformation into secondary acute myeloid leukemia (sAML). Recurrent mutations in ... ...

Abstract	Background: Myelodysplastic syndromes (MDS) arise from somatic mutations acquired in hematopoietic stem and progenitor cells, causing cytopenias and predisposing to transformation into secondary acute myeloid leukemia (sAML). Recurrent mutations in spliceosome genes, including Methods: We identified candidate neoantigen epitopes from recurrent protein-coding mutations in the spliceosome genes Results: We identified two neoantigens created from a recurrent mutation in Conclusions: These data serve as proof-of-concept for developing precision medicine approaches that use neoantigen-directed T-cell receptor-transduced T cells to treat MDS and sAML.
MeSH term(s)	Humans ; Mice ; Animals ; CD8-Positive T-Lymphocytes ; Splicing Factor U2AF/genetics ; Splicing Factor U2AF/metabolism ; Antigens, Neoplasm ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/therapy ; Leukemia, Myeloid, Acute/metabolism ; Epitopes/metabolism
Chemical Substances	Splicing Factor U2AF ; Antigens, Neoplasm ; Receptors, Antigen, T-Cell ; Epitopes ; U2AF1 protein, human
Language	English
Publishing date	2023-12-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007490
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Article ; Online: Examining the impact of age on the prognostic value of ELN-2017 and ELN-2022 acute myeloid leukemia risk stratifications: a report from the SWOG Cancer Research Network.

Termini, Christina M / Moseley, Anna / Othus, Megan / Appelbaum, Frederick R / Chauncey, Thomas R / Erba, Harry P / Fang, Min / Lee, Stanley C / Naru, Jasmine / Pogosova-Agadjanyan, Era L / Radich, Jerald P / Willman, Cheryl L / Wu, Feinan / Meshinchi, Soheil / Stirewalt, Derek L

Haematologica

2023 Volume 108, Issue 11, Page(s) 3148–3151

MeSH term(s)	Humans ; Prognosis ; Leukemia, Myeloid, Acute/diagnosis ; Treatment Outcome ; Risk Assessment
Language	English
Publishing date	2023-11-01
Publishing country	Italy
Document type	Letter
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.282733
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Article: Fine-tuning PU.1.

Stirewalt, Derek L

Nature genetics

2004 Volume 36, Issue 6, Page(s) 550–551

MeSH term(s)	Animals ; Gene Dosage ; Gene Expression ; Hematopoiesis/genetics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Mice ; Mice, Mutant Strains ; Models, Genetic ; Proto-Oncogene Proteins/genetics ; Trans-Activators/genetics
Chemical Substances	Proto-Oncogene Proteins ; Trans-Activators ; proto-oncogene protein Spi-1
Language	English
Publishing date	2004-06
Publishing country	United States
Document type	Comment ; News
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/ng0604-550
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Receptor tyrosine kinase alterations in AML - biology and therapy.

Stirewalt, Derek L / Meshinchi, Soheil

Cancer treatment and research

2010 Volume 145, Page(s) 85–108

Abstract: Acute myeloid leukemia (AML) is the most common form of leukemia in adults, and despite some recent progress in understanding the biology of the disease, AML remains the leading cause of leukemia-related deaths in adults and children. AML is a complex ... ...

Abstract	Acute myeloid leukemia (AML) is the most common form of leukemia in adults, and despite some recent progress in understanding the biology of the disease, AML remains the leading cause of leukemia-related deaths in adults and children. AML is a complex and heterogeneous disease, often involving multiple genetic defects that promote leukemic transformation and drug resistance. The cooperativity model suggests that an initial genetic event leads to maturational arrest in a myeloid progenitor cell, and subsequent genetic events induce proliferation and block apoptosis. Together, these genetic abnormalities lead to clonal expansion and frank leukemia. The purpose of this chapter is to review the biology of receptor tyrosine kinases (RTKs) in AML, exploring how RTKs are being used as novel prognostic factors and potential therapeutic targets.
MeSH term(s)	Adult ; Antineoplastic Agents/therapeutic use ; Drug Delivery Systems ; Forecasting ; Gene Duplication ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/enzymology ; Leukemia, Myeloid, Acute/genetics ; Models, Biological ; Mutation ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/physiology ; Oncogene Proteins, Fusion/antagonists & inhibitors ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/physiology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-kit/antagonists & inhibitors ; Proto-Oncogene Proteins c-kit/genetics ; Proto-Oncogene Proteins c-kit/physiology ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; fms-Like Tyrosine Kinase 3/antagonists & inhibitors ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/physiology
Chemical Substances	Antineoplastic Agents ; Neoplasm Proteins ; Oncogene Proteins, Fusion ; Protein Kinase Inhibitors ; FLT3 protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2010
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	0927-3042
ISSN	0927-3042
DOI	10.1007/978-0-387-69259-3_6
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Article ; Online: Gene expression changes in normal haematopoietic cells.

Lionberger, Jack M / Stirewalt, Derek L

Best practice & research. Clinical haematology

2009 Volume 22, Issue 2, Page(s) 249–269

Abstract: The complexity of the healthy haematopoietic system is immense, and as such, one must understand the biology driving normal haematopoietic expression profiles when designing experiments and interpreting expression data that involve normal cells. This ... ...

Abstract	The complexity of the healthy haematopoietic system is immense, and as such, one must understand the biology driving normal haematopoietic expression profiles when designing experiments and interpreting expression data that involve normal cells. This article seeks to present an organised approach to the use and interpretation of gene profiling in normal haematopoiesis and broadly illustrates the challenges of selecting appropriate controls for high-throughput expression studies.
MeSH term(s)	Aging/genetics ; Cell Differentiation ; Environmental Exposure ; Epigenesis, Genetic/physiology ; Female ; Gene Expression/drug effects ; Gene Expression/physiology ; Gene Expression Profiling ; Genetic Techniques ; Hematopoietic Stem Cells/physiology ; Hematopoietic System/cytology ; Hematopoietic System/physiology ; Humans ; Male ; Membrane Proteins/physiology ; Oligonucleotide Array Sequence Analysis ; Proteome/physiology ; Transcription Factors/physiology
Chemical Substances	Membrane Proteins ; Proteome ; Transcription Factors
Language	English
Publishing date	2009-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2048027-1
ISSN	1532-1924 ; 1521-6926
ISSN (online)	1532-1924
ISSN	1521-6926
DOI	10.1016/j.beha.2009.05.005
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Article: Verification of prognostic expression biomarkers is improved by examining enriched leukemic blasts rather than mononuclear cells from acute myeloid leukemia patients.

Pogosova-Agadjanyan, Era L / Hua, Xing / Othus, Megan / Appelbaum, Frederick R / Chauncey, Thomas R / Erba, Harry P / Fitzgibbon, Matthew P / Jenkins, Isaac C / Fang, Min / Lee, Stanley C / Moseley, Anna / Naru, Jasmine / Radich, Jerald P / Smith, Jenny L / Willborg, Brooke E / Willman, Cheryl L / Wu, Feinan / Meshinchi, Soheil / Stirewalt, Derek L

Biomarker research

2023 Volume 11, Issue 1, Page(s) 31

Abstract: Background: Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized ... ...

Abstract	Background: Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers. Methods: To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes. Results: Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells. Conclusions: This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.
Language	English
Publishing date	2023-03-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2699926-2
ISSN	2050-7771
ISSN	2050-7771
DOI	10.1186/s40364-023-00461-0
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Article ; Online: Long Noncoding RNA Expression Independently Predicts Outcome in Pediatric Acute Myeloid Leukemia.

Farrar, Jason E / Smith, Jenny L / Othus, Megan / Huang, Benjamin J / Wang, Yi-Cheng / Ries, Rhonda / Hylkema, Tiffany / Pogosova-Agadjanyan, Era L / Challa, Sneha / Leonti, Amanda / Shaw, Timothy I / Triche, Timothy J / Gamis, Alan S / Aplenc, Richard / Kolb, E Anders / Ma, Xiaotu / Stirewalt, Derek L / Alonzo, Todd A / Meshinchi, Soheil

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2023 Volume 41, Issue 16, Page(s) 2949–2962

Abstract: Purpose: Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene ... ...

Abstract	Purpose: Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML. Methods: To identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized Cox regression model of event-free survival (EFS), yielding a 37 lncRNA signature (lncScore). Discretized lncScores were correlated with initial and postinduction treatment outcomes using Cox proportional hazards models in validation sets. Predictive model performance was compared with standard stratification methods by concordance analysis. Results: Training set cases with positive lncScores had 5-year EFS and overall survival rates of 26.7% and 42.7%, respectively, compared with 56.9% and 76.3% with negative lncScores (hazard ratio, 2.48 and 3.16; Conclusion: Inclusion of the lncScore enhances predictive power of traditional cytogenetic and mutation-defined stratification in pAML with potential, as a single assay, to replace these complex stratification schemes with comparable predictive accuracy.
MeSH term(s)	Humans ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Leukemia, Myeloid, Acute/therapy ; Prognosis ; Treatment Outcome ; Mutation
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.22.01114
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hematopoietic stem cell transplantation for hematologic malignancies in older adults: geriatric principles in the transplant clinic.

Wildes, Tanya M / Stirewalt, Derek L / Medeiros, Bruno / Hurria, Arti

Journal of the National Comprehensive Cancer Network : JNCCN

2014 Volume 12, Issue 1, Page(s) 128–136

Abstract: Hematopoietic cell transplantation (HCT) provides a life-prolonging or potentially curative treatment option for patients with hematologic malignancies. Given the high transplant-related morbidity, these treatment strategies were initially restricted to ... ...

Abstract	Hematopoietic cell transplantation (HCT) provides a life-prolonging or potentially curative treatment option for patients with hematologic malignancies. Given the high transplant-related morbidity, these treatment strategies were initially restricted to younger patients, but are increasingly being used in older adults. The incidence of most hematologic malignancies increases with age; with the aging of the population, the number of potential older candidates for HCT increases. Autologous HCT (auto-HCT) in older patients may confer a slightly increased risk of specific toxicities (such as cardiac toxicities and mucositis) and have modestly lower effectiveness (in the case of lymphoma). However, auto-HCT remains a feasible, safe, and effective therapy for selected older adults with multiple myeloma and lymphoma. Similarly, allogeneic transplant (allo-HCT) is a potential therapeutic option for selected older adults, although fewer data exist on allo-HCT in older patients. Based on currently available data, age alone is not the best predictor of toxicity and outcomes; rather, the comorbidities and functional status of the older patient are likely better predictors of toxicity than chronologic age in both the autologous and allogeneic setting. A comprehensive geriatric assessment (CGA) in older adults being considered for either an auto-HCT or allo-HCT may identify additional problems or geriatric syndromes, which may not be detected during the standard pretransplant evaluation. Further research is needed to establish the utility of CGA in predicting toxicity and to evaluate the quality of survival in older adults undergoing HCT.
MeSH term(s)	Aged ; Aged, 80 and over ; Disease-Free Survival ; Female ; Geriatric Assessment ; Hematologic Neoplasms/epidemiology ; Hematologic Neoplasms/pathology ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Male ; Treatment Outcome
Language	English
Publishing date	2014-01-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2250759-0
ISSN	1540-1413 ; 1540-1405
ISSN (online)	1540-1413
ISSN	1540-1405
DOI	10.6004/jnccn.2014.0010
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Article: Comparison of Two Methods for Detecting Alternative Splice Variants Using GeneChip(®) Exon Arrays.

Fan, Wenhong / Stirewalt, Derek L / Radich, Jerald P / Zhao, Lueping

International journal of biomedical science : IJBS

2013 Volume 7, Issue 3, Page(s) 172–180

Abstract: The Affymetrix GeneChip Exon Array can be used to detect alternative splice variants. Microarray Detection of Alternative Splicing (MIDAS) and Partek(®) Genomics Suite (Partek(®) GS) are among the most popular analytical methods used to analyze exon ... ...

Abstract	The Affymetrix GeneChip Exon Array can be used to detect alternative splice variants. Microarray Detection of Alternative Splicing (MIDAS) and Partek(®) Genomics Suite (Partek(®) GS) are among the most popular analytical methods used to analyze exon array data. While both methods utilize statistical significance for testing, MIDAS and Partek(®) GS could produce somewhat different results due to different underlying assumptions. Comparing MIDAS and Partek(®) GS is quite difficult due to their substantially different mathematical formulations and assumptions regarding alternative splice variants. For meaningful comparison, we have used the previously published generalized probe model (GPM) which encompasses both MIDAS and Partek(®) GS under different assumptions. We analyzed a colon cancer exon array data set using MIDAS, Partek(®) GS and GPM. MIDAS and Partek(®) GS produced quite different sets of genes that are considered to have alternative splice variants. Further, we found that GPM produced results similar to MIDAS as well as to Partek(®) GS under their respective assumptions. Within the GPM, we show how discoveries relating to alternative variants can be quite different due to different assumptions. MIDAS focuses on relative changes in expression values across different exons within genes and tends to be robust but less efficient. Partek(®) GS, however, uses absolute expression values of individual exons within genes and tends to be more efficient but more sensitive to the presence of outliers. From our observations, we conclude that MIDAS and Partek(®) GS produce complementary results, and discoveries from both analyses should be considered.
Language	English
Publishing date	2013-05-15
Publishing country	United States
Document type	Journal Article
ISSN	1550-9702
ISSN	1550-9702
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Article ; Online: Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.

Clough, Courtnee A / Pangallo, Joseph / Sarchi, Martina / Ilagan, Janine O / North, Khrystyna / Bergantinos, Rochelle / Stolla, Massiel C / Naru, Jasmine / Nugent, Patrick / Kim, Eunhee / Stirewalt, Derek L / Subramaniam, Arvind R / Abdel-Wahab, Omar / Abkowitz, Janis L / Bradley, Robert K / Doulatov, Sergei

Blood

2021 Volume 139, Issue 13, Page(s) 2038–2049

Abstract: SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably ... ...

Abstract	SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces missplicing of ∼100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All 3 missplicing events reduce protein expression, notably occurring via 5' UTR alteration, and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated missplicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing RS formation.
MeSH term(s)	ATP-Binding Cassette Transporters ; Cell Differentiation/genetics ; Flavoproteins/genetics ; Flavoproteins/metabolism ; Humans ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Proteins/genetics ; Mutation ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/metabolism ; Phosphoproteins/genetics ; Protoporphyrinogen Oxidase/genetics ; Protoporphyrinogen Oxidase/metabolism ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism
Chemical Substances	ABCB7 protein, human ; ATP-Binding Cassette Transporters ; Flavoproteins ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins ; Phosphoproteins ; RNA Splicing Factors ; SF3B1 protein, human ; PPOX protein, human (EC 1.3.3.4) ; Protoporphyrinogen Oxidase (EC 1.3.3.4)
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021012652
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