Leukemic stem cell phenotype is associated with mutational profile in acute myeloid leukemia.

BACKGROUND/AIMS: Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear. METHODS: Here we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients. RESULTS: In secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML. CONCLUSION: LSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.

Induction of leukemic stem cell differentiation by aryl hydrocarbon receptor agonist and synergy with gilteritinib in FLT3-ITD + acute myeloid leukemia.

Leukemic stem cells (LSCs) are a major cause of treatment failure and recurrence of acute myeloid leukemia (AML). Targeting LSC is essential to developing a potential cure for patients with relapsed/refractory AML. Here we investigated the effect of aryl hydrocarbon receptor (AhR) signaling on AML stem/progenitor proportion and examined the combined effect of AhR agonist and tyrosine kinase inhibitor. The AhR agonist, 6-formylindolo[3,2-b]carbazole (FICZ), significantly decreased the LSC proportion and clonogenicity and increased differentiation markers in AML primary cells. Synergistic/additive effects of FICZ and gilteritinib, FMS-like tyrosine kinase 3 (FLT3) inhibitor, were confirmed in AML cells with FLT3-ITD. We present evidence that combination of both agents inhibits FLT3 downstream molecules and degrades clonogenicity. Collectively, our results suggest that FICZ not only compels LSC differentiation, but also enhances the efficacy of gilteritinib when combined. Clinical application of this combined approach may pave a new therapeutic strategy for patients with FLT3 mutated AML.