<i>NPM1</i> mutation but not <i>RUNX1</i> mutation or multilineage dysplasia defines a prognostic subgroup within de novo acute myeloid leukemia lacking recurrent cytogenetic abnormalities in the revised 2016 WHO classification

Weinberg, Olga K.; Gibson, Christopher J.; Blonquist, Traci M.; Neuberg, Donna; Pozdnyakova, Olga; Kuo, Frank C.; Ebert, Benjamin L.

doi:10.1002/ajh.24739

Cited by 11 publications

(12 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53. 12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53.…”

Section: Case Selectionmentioning

confidence: 99%

“…For all patients meeting inclusion criteria, we reviewed and classified data from targeted sequencing studies performed on bone marrow aspirates (n = 77) or peripheral blood (n = 14) specimens at the time of diagnosis, as previously described. 12,[25][26][27] were selected based on pathogenic involvement in myeloid malignancies. Genes assessed in all platforms were NPM1, FLT3, DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, BCOR, SETBP1, BCORL, SH2B3, SETD2, CREBBP, WT1, PHF6, CEBPA, RUNX1, ETV6, STAG2, PDS5B, RAD21, KRAS, NRAS, KIT, CBL, RIT1, PTPN11, NF1, JAK2, U2AF1, ZRSR2, PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53.…”

Section: Next-generation Sequencing Studies Performed At Diagnosis mentioning

confidence: 99%

See 1 more Smart Citation

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

et al. 2019

Self Cite

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 WHO classification, and is associated with a favorable prognosis. While previous studies have evaluated NPM1 in a binary fashion, we recently demonstrated a significant independent negative prognostic effect of high NPM1 mutant allele burden (VAF) at diagnosis in a cohort of de novo AML patients. Although the importance of minimal residual disease (MRD) monitoring in NPM1‐mutated AML has been well characterized, the potential relationship between diagnostic allele burden and MRD is unknown. We retrospectively evaluated for MRD at first remission (CR1). We used either next‐generation sequencing (NGS) [n = 71], and/or immunohistochemistry (IHC) for mutant NPM1 (NPM1c) [n = 60], in a subset of patients from our recently examined cohort. We identified a statistically significant positive correlation between the VAF at diagnosis, and at CR1 (Spearman r = 0.4, P = .006), and enrichment for MRD in high diagnostic VAF patients (P = .05), as previously defined. IHC‐positivity also correlated significantly with a higher median diagnostic NPM1 VAF (0.42 vs 0.39, P = .02), and with the VAF at CR1 (Spearman r = 0.7, P = .003). In multivariable analyses, both high diagnostic VAF (P = .003) and MRD (P = .02) were independent predictors of shorter event‐free survival (EFS). Our findings suggest a relationship between the NPM1 mutant allele burden at diagnosis, and the presence of MRD at first remission. Our findings support IHC as a potentially useful adjunctive tool for disease monitoring.

show abstract

“…12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53. 12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53.…”

Section: Case Selectionmentioning

confidence: 99%

Section: Next-generation Sequencing Studies Performed At Diagnosis mentioning

confidence: 99%

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Only red blood cell count was significantly lower in the patients in cluster-2 (4 × 10 9 /L) compared to cluster-1 (5 × 10 9 /L) (Table 1A). Additionally, frequencies of the recurrent genetic abnormalities according to WHO classification [17] and mutational profiles were similar between the two clusters (Table 1B). Only FLT3-ITD mutation frequency was higher in cluster-2 patients than cluster-1 although it was not significant.…”

Section: Comparison Of Patient Characteristics and Outcome Between Twmentioning

confidence: 73%

Peptide microarray of pediatric acute myeloid leukemia is related to relapse and reveals involvement of DNA damage response and repair

et al. 2019

View full text Add to dashboard Cite

The majority of acute myeloid leukemia (AML) patients suffer from relapse and the exact etiology of AML remains unclear. The aim of this study was to gain comprehensive insights into the activity of signaling pathways in AML. In this study, using a high-throughput PepChip™ Kinomics microarray system, pediatric AML samples were analyzed to gain insights of active signal transduction pathway. Unsupervised hierarchical cluster analysis separated the AML blast profiles into two clusters. These two clusters were independent of patient characteristics, whereas the cumulative incidence of relapse (CIR) was significantly higher in the patients belonging to cluster-2. In addition, cluster-2 samples showed to be significantly less sensitive to various chemotherapeutic drugs. The activated peptides in cluster-1 and cluster-2 reflected the activity of cell cycle regulation, cell proliferation, cell differentiation, apoptosis, PI3K/AKT, MAPK, metabolism regulation, transcription factors and GPCRs signaling pathways. The difference between two clusters might be explained by the higher cell cycle arrest response in cluster-1 patients and higher DNA repair mechanism in cluster-2 patients. In conclusion, our study identifies different signaling profiles in pediatric AML in relation with CIR involving DNA damage response and repair.

show abstract

“…However, this rate might be influenced by the fact that our study included only AML cases without a history of a prior myeloid neoplasm and without MDS-associated cytogenetic abnormalities. 2 , 17 Interestingly, Thol et al . and The Cancer Genome Atlas research network found a strong association between NPM1 mutations and mutations in cohesin genes, 2 , 17 and in our study 6 (31%) of 19 cases with cohesin mutations also had NPM1 mutations, and the latter were also associated with frequent megakaryocytes with separated nuclear lobes.…”

Section: Discussionmentioning

confidence: 99%

“… 2 , 17 Interestingly, Thol et al . and The Cancer Genome Atlas research network found a strong association between NPM1 mutations and mutations in cohesin genes, 2 , 17 and in our study 6 (31%) of 19 cases with cohesin mutations also had NPM1 mutations, and the latter were also associated with frequent megakaryocytes with separated nuclear lobes. RAS pathway mutations were frequently seen in our cohort, being present in 58% of the cases and, similar to cohesin pathway and NPM1 mutations, were associated with megakaryocytes with separated nuclear lobes.…”

Section: Discussionmentioning

confidence: 99%

Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities

et al. 2018

Self Cite

View full text Add to dashboard Cite

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with de novo AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted P)=0.046] were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any vs. no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS) (P=0.042), while RUNX1 (P=0.042), NF1 (P=0.040), frequent micromegakaryocytes (P=0.018) and presence of a subclone (P=0.002) were associated with shorter EFS. In multivariable modeling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS.

show abstract

NPM1 mutation but not RUNX1 mutation or multilineage dysplasia defines a prognostic subgroup within de novo acute myeloid leukemia lacking recurrent cytogenetic abnormalities in the revised 2016 WHO classification

Cited by 11 publications

References 6 publications

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

Peptide microarray of pediatric acute myeloid leukemia is related to relapse and reveals involvement of DNA damage response and repair

Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities

Contact Info

Product

Resources

About