Key Points• The core autophagy protein ATG4B is highly expressed in CML stem/progenitor cells and may be useful in predicting treatment response.• ATG4B knockdown reduces autophagy, impairs the survival of CML stem/progenitor cells, and sensitizes them to IM treatment.Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34 1 hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34 1 cells from chronicphase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34 1 CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naïve CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells. (Blood. 2014;123(23):3622-3634)

ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov).

Highlights d 45% of colon cancers sub-stochiometrically lose m 1 acp 3 J ribosomal RNA modification d 22+ distinct cancer types show hypo-modification of m 1 acp 3 J d The >1-billion-years-conserved m 1 acp 3 J is involved in ribosomal P site stability d Loss of m 1 acp 3 J modification drives heterogenous translation of RP mRNAs

Autophagy is an evolutionarily conserved cellular recycling process in cell homeostasis and stress adaptation. It confers protection and promotes survival in response to metabolic/environmental stress, and is upregulated in response to nutrient deprivation, hypoxia, and chemotherapies. Autophagy is also known to sustain malignant cell growth and contributes to cancer stem cell survival when challenged by cytotoxic and/or targeted therapies, a potential mechanism of disease persistence and drug resistance that has gathered momentum. However, different types of human leukemia utilize autophagy in complex, context-specific manners, and the molecular and cellular mechanisms underlying this process involve multiple protein networks that will be discussed in this review. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of cancer therapies. Chloroquine and other lysosomal inhibitors have spurred initiation of clinical trials and demonstrated that inhibition of autophagy restores chemosensitivity of anticancer drugs, but with limited autophagy-dependent effects. Intriguingly, several autophagy-specific inhibitors, with better therapeutic indexes and lower toxicity, have been developed. Promising preclinical studies with novel combination approaches as well as potential challenges to effectively eradicate drug-resistant cells, particularly cancer stem cells, in human leukemia are also detailed in this review.