A 17-gene stemness score for rapid determination of risk in acute leukaemia

Abstract

A rapid gene signature test (LSC17) that captures stem cell expression programs in acute myeloid leukaemia patients at diagnosis is associated with therapy response and survival, facilitating initial treatment stratification. The prevalence of stem cell features can influence the prognosis of acute myeloid leukaemia. In this report, the authors identify and validate a 17-gene leukemia stem cell (LSC) signature score, termed the LSC17 score, that captures the prevalence of stem cell expression programs in patients and their influence on clinical outcome. Further testing will determine if the signature can be incorporated into risk assessment algorithms to better define prognosis of patient subsets in acute myeloid leukaemia. Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML)1. After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories2,3. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors4. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials5. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance6,7,8,9,10. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC+ and 89 LSC− cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.

Cite this article

Ng, S., Mitchell, A., Kennedy, J. et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature 540, 433–437 (2016). https://doi.org/10.1038/nature20598

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