title: ATP depletion triggers acute myeloid leukemia differentiation through an ATR/Chk1 protein-dependent and p53 protein-independent pathway.
abstract: Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.
authors.affiliation: Invenio Therapeutics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Kalpana
authors.initials: K
authors.lastname: Gupta
authors.forename: James Prabhakar
authors.initials: JP
authors.lastname: Sharma
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.forename: Anju
authors.initials: A
authors.lastname: Agarwal
authors.forename: Abigail
authors.initials: A
authors.lastname: Glick
authors.forename: Youwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Munna
authors.initials: M
authors.lastname: Agarwal
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Agarwal
authors.forename: David N
authors.initials: DN
authors.lastname: Wald
mesh_terms: D000208:Acute Disease; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D020552:Comet Assay; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C485108:6-benzylthioinosine; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D013868:Thioinosine; C054852:7-hydroxystaurosporine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D000241:Adenosine