PMID- 36347832
OWN - NLM
STAT- MEDLINE
DCOM- 20221110
LR  - 20221222
IS  - 2044-5385 (Electronic)
IS  - 2044-5385 (Linking)
VI  - 12
IP  - 11
DP  - 2022 Nov 9
TI  - The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of 
      mitochondrial homeostasis and autophagy.
PG  - 151
LID - 10.1038/s41408-022-00747-w [doi]
LID - 151
AB  - The treatment of acute leukemia is challenging because of the genetic 
      heterogeneity between and within patients. Leukemic stem cells (LSCs) are 
      relatively drug-resistant and frequently relapse. Their plasticity and capacity 
      to adapt to extracellular stress, in which mitochondrial metabolism and autophagy 
      play important roles, further complicates treatment. Genetic models of 
      phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition 
      have demonstrated the relevance of these enzymes in mitochondrial homeostasis and 
      autophagic flux. Here, we uncovered the cellular and molecular effects of 
      THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced 
      cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane 
      potential, and the accumulation of acidic vesicular organelles. Protein 
      expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, 
      THZ-P1-2 induced cell differentiation and showed synergistic effects with 
      venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed 
      that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell 
      cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the 
      TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34(+) cells 
      suggest a favorable therapeutic window. Our study provides insights into the 
      pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and 
      autophagy, shedding light on a new class of drugs for acute leukemia.
CI  - (c) 2022. The Author(s).
FAU - Lima, Keli
AU  - Lima K
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
AD  - Department of Pharmacology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Pereira-Martins, Diego Antonio
AU  - Pereira-Martins DA
AUID- ORCID: 0000-0002-3302-4311
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - de Miranda, Livia Bassani Lins
AU  - de Miranda LBL
AD  - Department of Pharmacology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Coelho-Silva, Juan Luiz
AU  - Coelho-Silva JL
AUID- ORCID: 0000-0001-8384-6551
AD  - Department of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical 
      School, University of Sao Paulo, Ribeirao Preto, Brazil.
FAU - Leandro, Giovana da Silva
AU  - Leandro GDS
AD  - Department of Microbiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Weinhauser, Isabel
AU  - Weinhauser I
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Cavaglieri, Rita de Cassia
AU  - Cavaglieri RC
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
FAU - Leal, Aline de Medeiros
AU  - Leal AM
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
FAU - da Silva, Wellington Fernandes
AU  - da Silva WF
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
FAU - Lange, Ana Paula Alencar de Lima
AU  - Lange APAL
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
FAU - Velloso, Elvira Deolinda Rodrigues Pereira
AU  - Velloso EDRP
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil.
FAU - Griessinger, Emmanuel
AU  - Griessinger E
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Hilberink, Jacobien R
AU  - Hilberink JR
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Ammatuna, Emanuele
AU  - Ammatuna E
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Huls, Gerwin
AU  - Huls G
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Schuringa, Jan Jacob
AU  - Schuringa JJ
AD  - Department of Experimental Hematology, Cancer Research Center Groningen, 
      University Medical Center Groningen, University of Groningen, Groningen, 
      Netherlands.
FAU - Rego, Eduardo Magalhaes
AU  - Rego EM
AD  - Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in 
      Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology 
      Division, Faculdade de Medicina, University of Sao Paulo, Sao Paulo, Brazil. 
      eduardo.rego@fm.usp.br.
FAU - Machado-Neto, Joao Agostinho
AU  - Machado-Neto JA
AUID- ORCID: 0000-0002-2937-8109
AD  - Department of Pharmacology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil. jamachadoneto@usp.br.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221109
PL  - United States
TA  - Blood Cancer J
JT  - Blood cancer journal
JID - 101568469
SB  - IM
MH  - Humans
MH  - Chromatography, Liquid
MH  - *Tandem Mass Spectrometry
MH  - Autophagy
MH  - *Leukemia, Myeloid, Acute/drug therapy/metabolism
MH  - Apoptosis
MH  - Homeostasis
PMC - PMC9643393
COIS- The authors declare no competing interests.
EDAT- 2022/11/09 06:00
MHDA- 2022/11/11 06:00
PMCR- 2022/11/09
CRDT- 2022/11/08 23:12
PHST- 2022/08/31 00:00 [received]
PHST- 2022/10/20 00:00 [accepted]
PHST- 2022/10/17 00:00 [revised]
PHST- 2022/11/08 23:12 [entrez]
PHST- 2022/11/09 06:00 [pubmed]
PHST- 2022/11/11 06:00 [medline]
PHST- 2022/11/09 00:00 [pmc-release]
AID - 10.1038/s41408-022-00747-w [pii]
AID - 747 [pii]
AID - 10.1038/s41408-022-00747-w [doi]
PST - epublish
SO  - Blood Cancer J. 2022 Nov 9;12(11):151. doi: 10.1038/s41408-022-00747-w.