The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial

Grimwade, David; Walker, Helen M.; Oliver, Fiona; Wheatley, Keith; Harrison, Christine J.; Harrison, Gill; Rees, John H.; Hann, Ian; Stevens, R. F.; Burnett, Alan Kenneth; Goldstone, Anthony H.

doi:10.1182/blood.v92.7.2322.2322_2322_2333

Cited by 76 publications

(45 citation statements)

References 33 publications

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“…All cases showed five or more copies of RUNX1 probe signals. Patient 1 displayed a highly complex karyotype of 45,XX,der(3)inv(3)(p25q25)add(3) (q11.2),-5,-7,+12,-14,add(14)(p11.2),+19,hsr(21) (q22) [3]/45,sl,-4,-12,+ r,+ mar [15]/46,sdl1,+ 8 [2] in three clones, each having monosomy 5 and 7 and an hsr on chromosome 21 (Fig. 1a).…”

Section: Karyotype and Fish Resultsmentioning

confidence: 99%

“…Acute myeloid leukemia (AML) is a genetically heterogeneous disease including several distinct subtypes based on cytogenetic and molecular characteristics [1,2]. Chromosomal and molecular genetic characteristics are a major feature for risk stratification to predict outcomes and guide treatment selection [3]. Although 5-year survival of adult AML has improved in the past decades due to advances in treatment, including targeted therapies and risk-adapted regimens, more than two-thirds of AML patients do not survive beyond 5 years and most relapse [4].…”

Section: Introductionmentioning

confidence: 99%

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21q22 amplification detection in three patients with acute myeloid leukemia: cytogenomic profiling and literature review

et al. 2022

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Background 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized. Case presentation Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks. Conclusions Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes.

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Section: Karyotype and Fish Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

21q22 amplification detection in three patients with acute myeloid leukemia: cytogenomic profiling and literature review

et al. 2022

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“…Efforts to advance our understanding of molecular alterations in pediatric AML 3,4,15,17,22,44,51 have revealed profound heterogeneity and improved understanding for how mutations and structural alterations impact treatment outcome. In the current study, we revealed that these molecular alterations share a close relationship with LSC gene expression, wherein LSC genes can accurately discriminate between AML molecular subtypes on the basis of unsupervised clustering alone.…”

Section: Discussionmentioning

confidence: 99%

“…Acute myeloid leukemia (AML) remains a therapeutic challenge with high mortality rates despite intensive and myeloablative therapies 1,2 . Structural and sequence alterations have been linked to outcomes in AML and have been used for risk-based therapy allocation with modest success [3][4][5][6][7][8][9][10] . However, given the vast heterogeneity of AML, conventional cytogenetic and molecular (cytomolecular) biomarkers have not yielded a robust prognostic model to date.…”

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confidence: 99%

Integrated Stem Cell Signature and Cytomolecular Risk Determination in Pediatric Acute Myeloid Leukemia

Huang

Smith

Ries

et al. 2020

Blood

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Acute myeloid leukemia (AML) remains a therapeutic challenge with high mortality rates despite intensive and myeloablative therapies. Structural and sequence alterations have been linked to outcomes in pediatric AML and have been used for risk-based therapy allocation with modest success. Given the vast heterogeneity of AML, conventional cytogenetic and mutational (cytomolecular) biomarkers have not yielded a robust prognostic model: nearly one-third of pediatric patients deemed "low risk" relapse and, inversely, approximately one-third of those in "high risk" categories have favorable outcomes. AML studies in adults previously identified a leukemia stem cell score (LSC17) that was highly prognostic across five independent cohorts comprised of adult patients with diverse AML subtypes (n = 908). We reasoned that incorporating a similar scoring system in pediatric AML would lead to improved prognostic risk models. To assess for the effects of LSC17 on pediatric AML, we leveraged transcriptome sequencing data from bone marrow aspirates and peripheral blood collected from 1,503 children, adolescents, and young adults with AML at the time of diagnosis. Patients were enrolled on one of three upfront phase III Children's Oncology Group trials spanning the past three decades: CCG-2961, AAML0531, and AAML1031. In aggregate, patients with a high LSC17 score had an event free survival (EFS) of 36.9 ± 3.5% at 5 years from diagnosis compared to 55.3 ± 3.7% for those with low LSC17 scores (p < 0.0001). (Figure 1A) LSC17 scores were also associated with adverse overall survival (OS): 51.9 ± 3.9% versus 73.8 ± 3.5% (p < 0.0001) (data not shown). Intriguingly, we found that LSC17 scores significantly cluster within fusion groups and that median LSC17 scores closely correlate with survival based on fusion status (Figure 1B). Thus, when the impact of LSC17 scores was evaluated in the context of established cytomolecular risk groups, LSC17 scores were no longer predictive of outcome (Figure 1C). We then asked whether LSC gene expression data could be utilized to generate a more robust risk classification schema in the context of disease defining structural variants. Importantly, AMLs diagnosed in children, adolescents, and young adults are associated with frequent driver gene fusion alterations that also play an important role in risk stratification and transcriptional landscape (Figure 1D). We went on to confirm that AML fusion groups occupy distinct transcriptional stages of hematopoietic stem cell and myeloid progenitor maturation based on gene set enrichment analysis (GSEA) using normal hematopoiesis transcriptome experiments as their reference (data not shown). To develop more predictive biomarkers related to stemness, we used the 54 original LSC genes identified by Ng S, et al. and performed linear regression based on a least absolute shrinkage and selection operator (LASSO) algorithm to fit a Cox regression model for patients within each fusion group. The study population was divided into discovery (n = 752) and validation (n = 752) cohorts using stratified randomization based on fusion status (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A, NUP98, CBFA2T3-GLIS2, and Other/None). In the discovery cohort, we identified distinct LSC signatures that best distinguished outcome cohorts in patients with conventional high/standard risk disease (KMT2A, NUP98, and Other/None fusions) (Figure 1E). For patients deemed favorable risk (RUNX1-RUNX1T1 and CBFB-MYH11 or core binding factor/CBF), LSC signatures were not reliably predictive based on "leave one out" cross validation. Therefore, we performed multivariable analysis incorporating clinical, mutational, and transcriptional signatures to determine the factors that best discriminated outcomes with CBF AML, and found GLIS2-like transcriptional signatures were most predictive. These cytomolecular and LSC (CM-LSC) biomarkers were then combined to build a robust risk determination model that was then validated in an independent cohort (Figure 1F). This study demonstrates that a 54 LSC gene expression panel can enhance the predictive power of conventional cytomolecular markers and can more effectively partition patients into risk groups. Figure 1 Disclosures Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019).

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“…Based on genetic abnormalities, the European Leukemia Network (ELN) risk stratification system classifies AML patients into three risk groups: favorable, intermediate, and adverse (Table S1) (6). The cytogenetic abnormalities associated with AML are recognized as being the most valuable prognostic factors (7). However, cytogenetically normal AML (CN-AML) represents the largest AML subset, comprising 45%-60% of all cases (8,9).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model

et al. 2021

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Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.

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The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial

Cited by 76 publications

References 33 publications

21q22 amplification detection in three patients with acute myeloid leukemia: cytogenomic profiling and literature review

21q22 amplification detection in three patients with acute myeloid leukemia: cytogenomic profiling and literature review

Integrated Stem Cell Signature and Cytomolecular Risk Determination in Pediatric Acute Myeloid Leukemia

Prognostic Prediction of Cytogenetically Normal Acute Myeloid Leukemia Based on a Gene Expression Model

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