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1.
Cancer Sci ; 114(8): 3247-3258, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37197765

RESUMO

Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML-specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34+ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol-3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), rate-limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol-3-phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM-inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM-mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target.


Assuntos
Leucemia Mieloide Aguda , Dinâmica Mitocondrial , Humanos , Glicerol , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Aciltransferases , Fosfatos
2.
Blood Adv ; 7(10): 2053-2065, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-36745103

RESUMO

The activation of ß-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant ß-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3-expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates ß-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.


Assuntos
Leucemia Mieloide Aguda , Via de Sinalização Wnt , Humanos , Receptor Celular 2 do Vírus da Hepatite A/genética , beta Catenina/metabolismo , Leucemia Mieloide Aguda/genética , Células-Tronco Hematopoéticas/metabolismo , Ligantes
3.
Blood Adv ; 7(14): 3592-3603, 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-36044390

RESUMO

Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia-specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.


Assuntos
Aminoácidos de Cadeia Ramificada , Leucemia Mieloide Aguda , Humanos , Aminoácidos de Cadeia Ramificada/metabolismo , Complexo Repressor Polycomb 2 , Transaminases/metabolismo , Cetoácidos
4.
Rinsho Ketsueki ; 63(5): 353-362, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35662157

RESUMO

Recent studies have demonstrated that cancer-specific metabolism plays a crucial role in a variety of malignancies, including acute myeloid leukemia (AML). To identify a novel therapeutic target for AML, we conducted a metabolite screen on AML cells and normal hematopoietic stem/progenitor cells (HSPCs) and detected that the metabolism of glycerol-3-phosphate (G3P) is reprogrammed in AML. Glycerol-3-phosphate acyltransferases (GPATs), the first and rate-limiting enzymes in the lipid biosynthesis pathway, convert G3P into lysophosphatidic acid (LPA). Among various GPAT isozymes, GPAT1 was highly expressed in AML cells and silencing it inhibited the cell growth of AML. GPAT1 is located on the outer membrane of the mitochondria and regulates mitochondrial fusion and oxidative phosphorylation (OXPHOS). Silencing GPAT1 promoted mitochondrial fission and reduced OXPHOS. In AML, the GPAT1 inhibitor also suppressed cell proliferation and mitochondrial metabolism. However, this inhibitor had no effect on normal hematopoiesis in vivo. In conclusion, these findings indicate that targeting GPAT1 may be a promising therapeutic strategy for AML, since it suppresses leukemia-specific metabolism without impairing normal HSPCs.


Assuntos
Glicerol , Leucemia Mieloide Aguda , Humanos , Glicerol/metabolismo , Glicerol/uso terapêutico , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mitocôndrias/metabolismo , Fosfatos/metabolismo , Fosfatos/uso terapêutico
5.
Blood ; 135(24): 2146-2158, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32219443

RESUMO

Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aromatase/metabolismo , Fatores Imunológicos/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Células HEK293 , Humanos , Células K562 , Masculino , Megacariócitos/efeitos dos fármacos , Megacariócitos/patologia , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Mielopoese/fisiologia , Especificidade por Substrato , Trombocitopenia/patologia
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