News - STAG2 mutation

Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts. (PubMed, Cells)

Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin.

3 days ago

Journal • Synthetic lethality

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • STAG2 (Stromal Antigen 2) • RAD21 (RAD21 Cohesin Complex Component) • SMC1A (Structural Maintenance Of Chromosomes 1A)

MYC expression • STAG2 mutation

LY2090314

11d

Pemigatinib After Chemotherapy for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

11 days ago

Trial completion date • Trial primary completion date

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • MECOM (MDS1 And EVI1 Complex Locus) • NUP214 (Nucleoporin 214) • GATA2 (GATA Binding Protein 2) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DEK (DEK Proto-Oncogene) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • FLT3 mutation • RUNX1 mutation • ASXL1 mutation • EZH2 mutation • MLL rearrangement • SRSF2 mutation • U2AF1 mutation • BCOR mutation • Chr del(5q) • STAG2 mutation • FLT3 wild-type • Chr t(9;11) • ZRSR2 mutation

cytarabine • Pemazyre (pemigatinib) • daunorubicin • Starasid (cytarabine ocfosfate)

25d

Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes. (PubMed, Blood Adv)

By investigating the Genomics of Drug Sensitivity in Cancer (GDSC) database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

25 days ago

Journal

TP53 (Tumor protein P53) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • STAG2 (Stromal Antigen 2) • PTK7 (Protein Tyrosine Kinase 7) • MAST4 (Microtubule Associated Serine/Threonine Kinase Family Member 4) • PAK6 (P21 (RAC1) Activated Kinase 6)

TP53 mutation • STAG2 mutation

Inlyta (axitinib) • taselisib (GDC-0032)

27d

Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes. (PubMed, Nat Commun)

While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.

27 days ago

Journal • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • RUNX1 (RUNX Family Transcription Factor 1) • TNFA (Tumor Necrosis Factor-Alpha) • STAG2 (Stromal Antigen 2)

RUNX1 mutation • STAG2 mutation

Venclexta (venetoclax)

RAD21 mutations in acute myeloid leukemia. (PubMed, Leuk Lymphoma)

This study showed that RAD21-mutated AML often associates with monocytic differentiation, CD7 expression, co-existing mutations in epigenetic regulators, a normal karyotype, and poor prognosis. Our findings provide additional insights into the morphologic, immunophenotypic, and genomic profile of RAD21 mutation-positive AML and suggest that RAD21 mutations should be evaluated for independent prognostic significance in AML.

1 month ago

Journal

STAG2 (Stromal Antigen 2) • RAD21 (RAD21 Cohesin Complex Component) • CD7 (CD7 Molecule)

STAG2 mutation • RAD21 mutation • CD7 expression

Mapping of DDX11 genetic interactions defines sister chromatid cohesion as the major dependency. (PubMed, G3 (Bethesda))

We confirm synthetic lethal relationships between DDX11 and the tumour suppressor cohesin subunit STAG2, which is frequently mutated in several cancer types and the kinase HASPIN. This screen highlights the importance of cohesion in cells lacking DDX11 and suggests DDX11 may be a therapeutic target for tumours with mutations in STAG2.

1 month ago

Journal

STAG2 (Stromal Antigen 2)

STAG2 mutation

2ms

Clinical and prognostic characteristics of pediatric acute myeloid leukemia with myelodysplasia-related changes under different diagnostic criteria (PubMed, Zhonghua Er Ke Za Zhi)

Twenty-seven children (10.4%) were eventually diagnosed with AML-MRC according to WHO 2022 criteria, their 2-year OS rate were worse than 233 non-AML-MRC children ((60.8±11.1)% vs. (94.5±1.6)%, χ2=24.49,P<0.001), and there was no statistically significant difference in EFS rate between two groups at 2 years ((55.1±10.8)% vs. (70.1±3.2)%, χ2=2.44, P=0.119). Compared with the 2022 WHO diagnostic criteria, the survival rates of children with AML-MRC under the 2016 WHO diagnostic criteria were worse than that of children without MRC.The new version of the AML-MRC diagnostic criteria emphasizes the importance of genes.

2 months ago

Journal

RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • STAG2 (Stromal Antigen 2) • SH2B3 (SH2B Adaptor Protein 3)

STAG2 mutation

3ms

STAG2: Computational Analysis of Missense Variants Involved in Disease. (PubMed, Int J Mol Sci)

In the present work, we model the structure of 12 missense variants described for STAG2, as well as two other variants of NIPBl and two of RAD21 located at STAG2 interaction zone, and then analyze their behavior through molecular dynamic simulations, comparing them with the same simulation of the wild-type protein. This will allow the effects of variants to be rationalized at the atomic level and provide clues as to how STAG2 functions in the cohesin complex.

3 months ago

Journal

STAG2 (Stromal Antigen 2) • RAD21 (RAD21 Cohesin Complex Component)

STAG2 mutation

3ms

Characterization of a Preclinical In Vitro Model Derived from a SMARCA4-Mutated Sinonasal Teratocarcinosarcoma. (PubMed, Cells)

Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

3 months ago

Preclinical • Journal

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • TET2 (Tet Methylcytosine Dioxygenase 2) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • NOTCH3 (Notch Receptor 3) • STAG2 (Stromal Antigen 2) • ARID2 (AT-Rich Interaction Domain 2) • WNT7A (Wnt Family Member 7A)

TET2 mutation • SMARCA4 mutation • STAG2 mutation

Ibrance (palbociclib) • Ezharmia (valemetostat)

4ms

Prognosis and risk factors for ASXL1 mutations in patients with newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. (PubMed, Cancer Med)

Our study indicated that mutations in G646W or RUNX1 co-mutations are closely associated with a dismal clinical outcome in patients with AML and MDS harboring ASXL1 . Considering the poor prognosis and risk factors in patients with ASXL1 , more available treatments should be pursued.

4 months ago

Journal

NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1)

NRAS mutation • RUNX1 mutation • ASXL1 mutation • EZH2 mutation • SRSF2 mutation • STAG2 mutation

5ms

Parallel Monitoring of Measurable Residual Disease and Chimerism By NGS in Myelodysplastic Syndrome after Allogenic STEM Cell Transplant (ASH 2023)

NGS-based parallel detection of chimerism and MRD in MDS is feasible and has high applicability and sensitivity, with several advantages compared to traditional methods. Nevertheless, further research and a larger cohort is necessary to draw meaningful conclusions.

5 months ago

Next-generation sequencing

STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1)

TP53 mutation • STAG2 mutation

5ms

Interactions between Iron Overload, Oxidative Stress, and Somatic Mutations in Myelodysplastic Syndromes; Evidence from the Literature (ASH 2023)

Of 31 mutations found in the IPSS-M, an additional four mutations found in familial predisposing conditions (DDX41, GATA2, CHEK2, SAMD9) were searched as was TET2, for a total of 35 mutations. Fifty-four references were identified. Fifty-three references were preclinical/translational in nature, with one case report (WT1).

5 months ago

Oxidative stress

TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • WT1 (WT1 Transcription Factor) • CHEK2 (Checkpoint kinase 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • ERFE (Erythroferrone)

TP53 mutation • NRAS mutation • TET2 mutation • SF3B1 mutation • CBL mutation • CHEK2 mutation • U2AF1 mutation • STAG2 mutation

5ms

CUX1mut Acute Myeloid Leukemia As a Distinct Biological Entity: An Analysis of Clinical Outcomes and Implications (ASH 2023)

In patients treated with intensive cytarabine-based inductions, the median overall survival was 26...Two patients with CUX1mut AML were treated with first-line venetoclax and a hypomethylating agent...These findings may explain a higher proportion of patients harboring CUX1 mutations that have ELN 2022 adverse-risk disease. While we did not detect any significant survival differences between patients with and without CUX1 mutations, larger cohorts are needed to confirm the prognostic impact of these rare mutations in AML.

5 months ago

Clinical • Clinical data

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2) • CUX1 (cut like homeobox 1)

FLT3-ITD mutation • STAG2 mutation • CUX1 mutation

Venclexta (venetoclax) • cytarabine

5ms

Characterization of Cases with the Rare Cytogenetic Abnormality I(7)(p10) Reveals an Association with IDH2 Mutated Acute Myeloid Leukemia (ASH 2023)

(1) The rare but recurrent cytogenetic aberration i(7)(p10) is mainly found in AML, where associations with mutations in IDH2, DNMT3A and BCOR were observed. By contrast, other AML-defining mutations ( NPM1, FLT3-ITD, CEPBA) were largely absent, further no defining fusions/rearrangements or a complex karyotype were detected. (2) The vast majority of patients were female and younger than patients with IDH2 mutation without i(7)(p10).

5 months ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ARG1 (Arginase 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • DNMT3A mutation + IDH mutation

5ms

Lessons of Nature in Trisomy-8 MDS and AML: Determinants of Clonal Drive (ASH 2023)

8 itself. Indeed, we found transcriptomic changes pertinent to +8 MDS whose role in driving leukemogenesis and interaction with specific myeloid drivers needs to be confirmed by future experimentations on cellular and murine models.

5 months ago

IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • NSD3 (Nuclear Receptor Binding SET Domain Protein 3) • BAG4 (BAG Cochaperone 4) • PVT1 (Pvt1 Oncogene) • LY96 (Lymphocyte Antigen 96)

FLT3 mutation • DNMT3A mutation • RUNX1 mutation • U2AF1 mutation • STAG2 mutation

5ms

Genomic Analyses Unveil the Pathogenesis and Inform on Therapeutic Targeting in KMT2A-PTD AML (ASH 2023)

Given the results obtained with menin inhibitors in KMT2A-rearranged and NPM1-mutated AML, our findings open an opportunity for exploiting a therapeutic vulnerability in all HOX-AML including KMT2A-PTD AML or AML with high MEN1 expression. Since HOX-AML highly express genes according to the HOX differentiation profile, stage-specific surface proteins coded by these genes would be promising targets.

5 months ago

Genomic analysis

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD276 (CD276 Molecule) • SRSF2 (Serine and arginine rich splicing factor 2) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule) • STAG2 (Stromal Antigen 2) • CD14 (CD14 Molecule) • LILRB4 (Leukocyte Immunoglobulin Like Receptor B4) • MEN1 (Menin 1) • CD1D (CD1d Molecule) • CD86 (CD86 Molecule) • HOXB2 (Homeobox B2) • NKX2-3 (NK2 Homeobox 3)

NPM1 mutation • TET2 mutation • KMT2A rearrangement • MLL rearrangement • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • MLL mutation • MLL translocation • KMT2A expression • KMT2A-PTD • CD1D expression

5ms

NGS Profile and the Mathematical Prediction Model for Venetoclax Combination Therapy in HM-Screen-Japan 02 Study (ASH 2023)

Introduction Azacitidine and venetoclax combination therapy (Aza/Ven) is a novel strategy for acute myeloid leukemia (AML). Our mathematical model, involving gene mutations and WT1, could efficiently predict the response of Aza/Ven, which may support the selection of 1 st line treatment. In conclusion, our study revealed the genetic landscape of real-world Aza/Ven therapy and provided a potential prognostic model.

5 months ago

Combination therapy • Next-generation sequencing

TP53 (Tumor protein P53) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • IDH2 mutation • NPM1 mutation • RUNX1 mutation • ASXL1 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • CEBPA mutation • STAG2 mutation • WT1 mutation • ZRSR2 mutation

Venclexta (venetoclax) • azacitidine

5ms

The consequences of cohesin mutations in myeloid malignancies. (PubMed, Front Mol Biosci)

We hypothesize that this points to changes in gene expression as disease-promoting mechanism and summarize the current state of knowledge on affected genes and pathways. Finally, we discuss potential strategies for targeting cohesion-deficient disease cells.

5 months ago

Review • Journal

STAG2 (Stromal Antigen 2)

STAG2 mutation

5ms

STAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition. (PubMed, Adv Sci (Weinh))

Importantly, STAG2 expression correlates with poor prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2-mutant tumors is elucidated.

5 months ago

Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • STAG2 (Stromal Antigen 2) • BARD1 (BRCA1 Associated RING Domain 1) • KMT5A (Lysine Methyltransferase 5A)

STAG2 mutation

5ms

COMUTATIONAL PATTERNS IN FGFR3-ALTERED NON-MUSCLE INVASIVE BLADDER CANCER INFLUENCE RECURRENCE AND PROGRESSION (SUO 2023)

As Erdafitinib, an FGFR1-4 inhibitor, has recently been approved for locally advanced and metastatic bladder cancer, numerous trials that assess the role and efficacy of FGFR inhibitors in the treatment of non-muscle-invasive disease have commenced... Trials of FGFR-inhibitors are ongoing in NMIBC. We predict that the diversity of response to these drugs in FGFR3-altered NMIBC will be dependent on co-mutational patterns, and identified three co-alterations (CDKN1A, CDKN2A, TP53) that affect the high-grade recurrence-free survival and clinical progression-free survival of patients with FGFR3-altered tumors. Future studies regarding the effect of these and other co-alterations on recurrence, progression, metastasis, and drug resistance in FGFR3-altered tumors are warranted and will provide more insight into the true efficacy of this new class of targeted therapies.

5 months ago

HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FGFR3 (Fibroblast growth factor receptor 3) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CREBBP (CREB binding protein) • KDM6A (Lysine Demethylase 6A) • STAG2 (Stromal Antigen 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • E2F3 (E2F transcription factor 3) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)

TP53 mutation • FGFR3 mutation • CDKN2A mutation • STAG2 mutation

MSK-IMPACT

Balversa (erdafitinib)

6ms

Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms. (PubMed, Leuk Lymphoma)

STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.

6 months ago

Journal

RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CSF3R (Colony Stimulating Factor 3 Receptor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1) • CUX1 (cut like homeobox 1)

ASXL1 mutation • SF3B1 mutation • CBL mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • SETBP1 mutation

6ms

Acute Myeloid Leukemia (AML) Patients with Myelodysplasia (MDS) Related-Gene Mutations in First Complete Remission (CR1) Found to Have Benefit from Allogeneic Hematopoietic Stem Cell Transplant (HCT) (ASH 2023)

In our cohort of 1228 AML patients, we have identified 278 AML patients with myelodysplasia-related gene mutations (22.6%). We have confirmed that allogeneic HCT in CR1 is strongly recommended in a subgroup of AML with myelodysplasia-related gene mutations based on the favorable impact of HCT in CR1 on RFS from the present study. This result supports the urgent referral of this patient group for allogeneic HCT in CR1.

6 months ago

Clinical

IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

IDH1 mutation • NPM1 mutation • ASXL1 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • ZRSR2 mutation

6ms

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT) (ASH 2023)

Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

6 months ago

Clinical

TP53 (Tumor protein P53) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2)

TP53 mutation • ASXL1 mutation • SRSF2 mutation • STAG2 mutation • MLL-PTD

azacitidine • decitabine

6ms

The Genomic Landscape and Its Clinical Implication in NPM1-Mutated AML Patients: A Study within the AMLSG 09-09 Clinical Trial (ASH 2023)

In this trial, pts were assigned to intensive chemotherapy plus all-trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1mut AML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome.

6 months ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • TET2 mutation • U2AF1 mutation • STAG2 mutation • DNMT3A R882

Rydapt (midostaurin) • Mylotarg (gemtuzumab ozogamicin)

6ms

Genomic Characterization of Newly Diagnosed Acute Myeloid Leukemia in Patients Age 60 Years and Older; A Report from the Beat AML Master Trial (ASH 2023)

Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.

6 months ago

Clinical

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2)

TP53 mutation • FLT3-ITD mutation • IDH1 mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • SF3B1 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation

FoundationOne® Heme CDx • LeukoStrat® CDx FLT3 Mutation Assay

6ms

Secondary-Type Mutations Do Not Impact the Favorable Outcome of NPM1-Mutated Acute Myeloid Leukemia Patients – Results from a Large Cohort of Intensively Treated Patients (ASH 2023)

NPM1 mutations rank as the second most frequent mutations in AML and the most common in patients with a normal karyotype and serve as an established favorable prognostic marker. Our data from a large cohort demonstrate that additional STMs have no adverse effect on the clinical outcome of NPM1-mutated patients. As a result, these patients should still be considered ELN favorable risk.

6 months ago

Clinical

TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • NPM1 mutation • SF3B1 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation

6ms

Molecular and Cytogenetic Characteristics of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) in Patients Exposed to Chemotherapy (CT) and/or Radiation (XRT) (ASH 2023)

Secondary type mutations were not enriched in pts exposed to any particular CT class (alkylators 25%, TI 30%, antimetabolites 28%, cisplatin 24%, and taxanes 26%)...57.5% of pts were treated with HMA+venetoclax, 20.6% with 7+3, 8.8% with HIDAC regimen, 14.7% with CPX-351, 17.5% with HMA alone... In our pts with AML/MDS exposed to previous chemotherapy/XRT, we found (i) True adverse CG, TP53 and secondary type mutations were present in a subset of AML/MDS, thus suggesting that not all exposure has a t-MN like signature and therapy relatedness needs to be redefined by biological subgroups rather than exposure alone. (ii) OS of non-adverse CG (AML) was comparable to historical data in denovo AML again suggesting that not all AML/MDS after chemo/XRT exposure behaves like t-MN (iii) We found an association of shorter latency and antimetabolite and platinum exposure to TP53 mutations and needs further validation in a larger dataset.

6 months ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • GATA2 (GATA Binding Protein 2) • RAD21 (RAD21 Cohesin Complex Component) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2) • SMC1A (Structural Maintenance Of Chromosomes 1A)

TP53 mutation • KRAS mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation

Venclexta (venetoclax) • cisplatin • Vyxeos (cytarabine/daunorubicin liposomal formulation)

6ms

Comparison of the Prognostic Performance of European Leukemianet 2017 and 2022 Classifications in a Minority-Rich Population of Adult Patients with Acute Myeloid Leukemia (ASH 2023)

Subjects with FLT3-ITD mutation with unknown allele frequency or who did not receive standard of care midostaurin were excluded... Our study compares the performance of the ELN 2017 and 2022 risk classifications in a predominantly minority AML patient population. Limited by small numbers, we showed that, compared to ELN17, the ELN22 classification provided more predictable trends for CR, OS and EFS, but we were unable to detect statistically significant differences between the 2 scores' prediction. Continuous study of larger, inclusive patient cohorts will be important to validate the prognostication schemas in ethnically and racially diverse populations.

6 months ago

Clinical

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

TP53 mutation • FLT3-ITD mutation • ASXL1 mutation • SF3B1 mutation • EZH2 mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation

Rydapt (midostaurin)

6ms

Characteristics and Outcomes of Younger Adult Patients (Pts) with Myelodysplastic Syndromes (MDS): A Multicenter Retrospective Study (ASH 2023)

In this study, de novo MDS was seen in the majority of younger pts with MDS (both AYA and YA). Mutations in STAG2 and NRAS were more common in the AYA pts, while YA pts had MDS more enriched for TP53, DNMT3A, TET2, and splicing mutations. This study is still ongoing with a plan to compare the abovementioned groups to older pts (≥60 years) with MDS.

6 months ago

Retrospective data

TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • SF3B1 (Splicing Factor 3b Subunit 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2)

TP53 mutation • NRAS mutation • DNMT3A mutation • TET2 mutation • SF3B1 mutation • SRSF2 mutation • STAG2 mutation