A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes

Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence

“…Proof-of-principle experiments using preclinical xenograft models further demonstrated that LRC-targeting therapy effectively restrains features of leukemic re-growth post-chemotherapy. These targets of leukemic regeneration could not have been predicted by existing characterizations of leukemic disease, as cellular states of AML during this vulnerable regenerative period are distinct from therapy-naive LSCs (Eppert et al, 2011), early stages of cytoreduction post-therapy (Farge et al, 2017), or terminal phases of relapse (Ding et al, 2012;Hackl et al, 2015;Ho et al, 2016;Shlush et al, 2017) that have previously been studied.…”

“…Gene expression data for three AML patient-derived xenografts were obtained from publically available datasets (Farge et al, 2017) (GSE97631). Patient-level gene expression data were also obtained from publically accessible data sets for 11 paired diagnosis-relapse samples (Hackl et al, 2015) (GSE66525) and was combined with 4 paired diagnosis-relapse samples from our study . Batch correction was performed on sources of technical variation (array technologies and/or scan date).…”

“…Several studies have carefully evaluated the functional and molecular biology of overtly relapsed AML (Ding et al, 2012;Hackl et al, 2015;Ho et al, 2016;Shlush et al, 2017); however, little attention has been dedicated to exploring the initial stages…”

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

“…Using a clinically relevant chemotherapeutic model, we and others previously demonstrated that LSCs are not necessarily enriched in post-AraC residual AML, suggesting LSCs include both chemosensitive and chemoresistant stem cell sub-populations (Farge et al, 2017;Boyd et al, 2018). In order to identify new vulnerabilities in the chemoresistant LSC population that might be responsible for relapse, we analyzed transcriptomic data from three different studies that ( Figure 1A; Table S1): i) identi ed 134 genes overexpressed in functionally de ned LSC compared with a normal HSC counterpart (Eppert et al, 2011; GSE30377); ii) uncovered 114 genes of high expression associated with poor prognosis in AML (the Cancer Genome Atlas, AML cohort, 2013); and iii) selected 536 genes overexpressed at relapse compared to pairwise matched diagnosis samples (Hackl et al, 2015;GSE66525). Surprisingly, we found one unique gene common to these three independent transcriptomic datasets: CALCRL, encoding a G proteincoupled seven-transmembrane domain receptor poorly documented in cancer that has been recently described as associated with a poor prognosis in AML (Angenendt et al, 2019).…”

“…Although novel targeted therapies are holding great promises, eradicating drug tolerant/resistant AML cells after chemotherapy remains the major challenge in the treatment of AML. (Hackl et al, 2015;Ho et al, 2016). While it has been initially shown that LSCs may be less affected by chemotherapy than more mature populations (Jordan et al, 2006;Ishikawa et al, 2007;Thomas et al 2013), recent works demonstrated that the anti-AML chemotherapy cytarabine (AraC) might deplete the LSC pool in PDX models (Farge et al, 2017;Boyd et al, 2018).…”