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. 2018 Jul 19;8(8):68.
doi: 10.1038/s41408-018-0103-6.

High Expression of HMGA2 Independently Predicts Poor Clinical Outcomes in Acute Myeloid Leukemia

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Free PMC article

High Expression of HMGA2 Independently Predicts Poor Clinical Outcomes in Acute Myeloid Leukemia

Miriam Marquis et al. Blood Cancer J. .
Free PMC article

Erratum in

Abstract

In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Flow diagram of the study and discovery approach for identification of HMGA2.
The HMGA2 prognostic marker was identified from the RNA-sequenced samples of the Leucegene full cohort (n = 430). Criteria for marker selection were: best log-rank P values to discriminate between poor vs good survivors based on the 75th percentile of expression (in RPKM values) for each gene, high dynamic range, bimodal distribution of gene expression values, and gene expression values above one RPKM. Development, analytical, and clinical validation of the HMGA2 RT-qPCR test were performed in the training cohort (n = 358). The Australian cohort (n = 70) was used to validate the RT-qPCR expression values. The HMGA2 test was externally validated in the NCRI AML17 cohort (n = 260). AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndromes; RPKM, reads per kilobase per million mapped reads; Tx, treatment
Fig. 2
Fig. 2. HMGA2 expression in AML cytogenetic and mutation subgroups.
Upper panel. The HMGA2 RT-qPCR test shows a large range of expression values among cytogenetic and mutation subgroups of the training cohort. HMGA2 expression levels evaluated by this test were normalized on the ABL1 control gene and expressed as NCN. The dotted line represents the assay cutoff established at 1100 NCN. Bottom panel. Frequency of patients classified in each subgroup according to the HMGA2 expression profile. Numbers in white represent HMGA2+ patients. ELN 2017 and cytogenetic risk subgroups were evaluated in the training cohort (n = 358), mutations were obtained by RNA sequencing in 263 samples of the training cohort. Abn., abnormal; biCEBPA, biallelic CEBPA mutations; ELN: European LeukemiaNet; HMGA2+ , high expression (≥1100 NCN); HMGA2−, low expression (<1100 NCN); NCN, Normalized Copy Numbers; NK, normal karyotype
Fig. 3
Fig. 3. High HMGA2 expression is associated with poor clinical outcomes in AML.
From left to right for a the training cohort, b NCRI AML17 validation cohort: overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR) curves according to high expression levels of HMGA2 (HMGA2 + , H+ ) compared with low expression levels (HMGA2−, H−). c OS and RFS curves for patients ( < 60 years) of the training cohort transplanted in first complete remission (n = 60). d OS curve for patients of the NCRI AML17 cohort not classified in the high-risk category (n = 157). The NCRI high-risk category is defined in the statistical methods section in the Supplementary Information., The P values were obtained by the log-rank test for comparison of OS and RFS curves and by Gray’s test for CIR curves
Fig. 4
Fig. 4. HMGA2 is an independent prognostic factor of poor outcome in AML.
Forest plot for multivariable analyses of overall survival, relapse-free survival and cumulative incidence of relapse in the training cohort. aHR, adjusted hazard ratio; CI, confidence intervals; HMGA2+ , high expression ( ≥ 1100 NCN); HMGA2-, low expression (<1100 NCN); HSCT, allogeneic hematopoietic stem cell transplantation; ITD, internal tandem duplication; WBC, white blood cell counts (×109/l). As the non-linear effect of age at diagnosis is represented jointly by the two coefficients (linear and quadratic), the interpretation of each coefficient separately is not appropriate and not shown in the figure
Fig. 5
Fig. 5. Utility of the HMGA2 test in intermediate cytogenetic risk AML patients.
a From left to right for patients of the training cohort classified in the intermediate cytogenetic risk category: overall survival (OS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR) curves according to high expression levels of HMGA2 (HMGA2 + , H+ ) compared with low expression levels (HMGA2−, H−). The P values were obtained by the log-rank test for comparison of OS and RFS curves and by Gray’s test for CIR curves. b Results for the six prognostically informative AML mutations (FLT3-ITD, NPM1, biallelic CEBPA, ASXL1, RUNX1, and TP53) in 41 H+ patients of the training cohort classified in the intermediate cytogenetic risk category are shown. Dark blue squares, presence of mutation; light blue squares, absence of mutation (WT); white squares, sample not tested or not sequenced for this mutation (NA); H + , high expression levels of HMGA2 (≥1100 NCN)

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References

    1. Dohner H, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447. doi: 10.1182/blood-2016-08-733196. - DOI - PMC - PubMed
    1. Grossmann V, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood. 2012;120:2963–2972. doi: 10.1182/blood-2012-03-419622. - DOI - PubMed
    1. Papaemmanuil E, et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 2016;374:2209–2221. doi: 10.1056/NEJMoa1516192. - DOI - PMC - PubMed
    1. Patel JP, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012;366:1079–1089. doi: 10.1056/NEJMoa1112304. - DOI - PMC - PubMed
    1. Metzeler KH, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–698. doi: 10.1182/blood-2016-01-693879. - DOI - PubMed

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