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

Abstract

Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). 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 categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. 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 trials. 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 resistance. 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.

MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing

“…Furthermore, gene set enrichment analysis 29,30 revealed that genes upregulated in human leukemia stem cells (LSCs) were more enriched in the leukemic bone marrow cells compared with the cultured cells, whereas genes downregulated in human LSCs were enriched in the cultured cells used for injection ( Figure 7B). 31 These data suggested that LSCs may be more abundant in AML in vivo than in cultured genomeedited cells, consistent with much shorter latencies for disease emergence in secondary transplanted mice ( Figure 6B). Thus, although t(9;11) may be sufficient for development of AML from genome-edited primary human cells, environmental or nongenetic factors may also influence disease progression.…”

Leukemic stem cells: identification and clinical application

“…In a recent study of Ng et al, the four CD34/CD38 defined cell populations of AML patients were sorted and were subsequently injected into mice and screened for their leukemia-initiating ability [13]. This exquisite approach confirmed that LSC activity was detected in all fractions; however, with a majority of CD34+ fractions, especially CD34+/CD38−, and minority of CD34− fractions containing LSC.…”

Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia

“…However, the SHB/PAX5/HDAC/BCORL1/TET1 network shows only limited resemblance to the poor prognosis of 17-gene stemness signature. 33 Currently, when addressing the functional significance of the overlap in co-expression between SHB/PAX5/HDAC7/ BCORL1/TET1 by ToppGene analysis, certain phenotypic characteristics can be observed. The most extensive list of biological functions appeared among SHB/PAX5 coexpressed genes in which functions relating to immune cell activation dominated.…”