Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

Baran, Natalia; Lodi, Alessia; Dhungana, Yogesh; Herbrich, Shelley M.; Collins, Meghan; Sweeney, Shannon R.; Pandey, Raju; Skwarska, Anna; Patel, Shraddha; Tremblay, Mathieu; Kuruvilla, Vinitha M.; Cavazos, Antonio; Kaplan, Mecit; Warmoes, Marc O.; Veiga, Diogo Troggian; Furudate, Ken; Rojas-Sutterin, Shanti; Haman, André; Gareau, Yves; Marinier, Anne; Ma, Helen; Harutyunyan, Karine G.; Daher, May; Garcia, Luciana Melo; Alatrash, Gheath; Piya, Sujan; Ruvolo, Vivian; Yang, Wentao; Shanmugavelandy, Sriram S.; Feng, Ningping; Gay, Jason; Du, Di; Yang, Jun J.; Hoff, Fieke W.; Kamiński, Marcin M.; Tomczak, Katarzyna; Davis, R. Eric; Herranz, Daniel; Ferrando, Adolfo A.; Jabbour, Elias; Francesco, Maria Emilia Di; Teachey, David T.; Horton, Terzah M.; Kornblau, S.; Rezvani, Katayoun; Sauvageau, Guy; Gagea, Mihai; Andreeff, Michael; Takahashi, Koichi; Marszalek, Joseph R.; Lorenzi, Philip L.; Yu, Jiyang; Tiziani, Stefano; Hoang, Trang; Konopleva, Marina

doi:10.1038/s41467-022-30396-3

Cited by 34 publications

(28 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, an upregulation of DLL4 was found. DLL4 is one of the most important regulators of NOTCH1, which is a driving oncogene in T‐ALL [ 18 , 19 ]. Additionally, the proto‐oncogene MYCN was upregulated together with SOX2 and YAP1, both markers for stem cell self‐renewal, reprogramming and homeostasis, as well as mechanistically promoting proliferation, survival, invasion/metastasis, cancer stemness and drug resistance [ 20 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia

Enlund

Sinha

Amor

et al. 2022

eJHaem

View full text Add to dashboard Cite

With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T-cell phenotype (T-ALL) and remains the major cause of death. The exact mechanism of relapse is currently not known. While contribution of RNA processing alteration has been linked to other hematological malignancies, its contribution in pediatric T-ALL may provide new insights. Almost all human genes express more than one alternative splice isoform. Thus, gene modulation producing a diverse repertoire of the transcriptome and proteome have become a significant molecular marker of cancer and a potential therapeutic vulnerability. To study this, we performed RNA-sequencing analysis on patient-derived samples followed by splice isoform-specific PCR. We uncovered a distinct RNA splice isoform expression pattern characteristic for relapse samples compared to the leukemia samples from the time of diagnosis. We also identified deregulated splicing and apoptosis pathways specific for relapse T-ALL. Moreover, patients with T-ALL displayed pro-survival splice isoform switching favoring pro-survival isoforms compared to normal healthy stem cells. Cumulatively, pro-survival isoform switching and DFFB isoform regulation of SOX2 and MYCN may play a role in T-ALL proliferation and survival, thus serving as a potential therapeutic option.

show abstract

Section: Resultsmentioning

confidence: 99%

Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia

Enlund

Sinha

Amor

et al. 2022

eJHaem

View full text Add to dashboard Cite

show abstract

“…The regulation of cellular metabolism by NOTCH has emerged in recent years as an exciting area of research. Although still quite unexplored, strong evidence supports the idea that NOTCH1 signaling promotes T-ALL growth by inducing the activation of anabolic pathways, including glycolysis, glutaminolysis, nucleotide biosynthesis, amino acids metabolism, ribosome biogenesis and protein activation [ 105 , 176 , 177 , 178 ]. On the contrary, NOTCH1 signaling inactivation switches metabolism to catabolic pathways, i.e., increased autophagy, ubiquitination and proteasomal degradation, and reduction in glycolytic and glutaminolytic flux [ 105 ].…”

Section: Molecular Collaborators Of Notch1 Signaling In T-all Pathoge...mentioning

confidence: 99%

“…To date, the best-known metabolic routes cooperating with oncogenic NOTCH1 signaling are MYC, PI3K/AKT, and RAS, and they will be discussed below. In addition, very recent studies have uncovered novel players involved in the metabolic reprogramming caused by aberrant NOTCH1 signals, such as the oxidative phosphorylation regulator mitochondrial complex I inhibitor [ 178 ] and the nucleotide biosynthesis regulator ubiquitin protein ligase E3 component N-recognin 7 (UBR7) [ 177 ]. Given that metabolic reprogramming is an essential mechanism of cancer cell outgrowth and dissemination [ 179 ], understanding the multiple levels of interconnections between NOTCH1 and metabolic pathways may help to delineate novel strategies to tackle exacerbated metabolic demand in T-ALL.…”

Section: Molecular Collaborators Of Notch1 Signaling In T-all Pathoge...mentioning

confidence: 99%

Notch Partners in the Long Journey of T-ALL Pathogenesis

Toribio

González-García

2023

IJMS

View full text Add to dashboard Cite

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease that arises from the oncogenic transformation of developing T cells during T-lymphopoiesis. Although T-ALL prognosis has improved markedly in recent years, relapsing and refractory patients with dismal outcomes still represent a major clinical issue. Consequently, understanding the pathological mechanisms that lead to the appearance of this malignancy and developing novel and more effective targeted therapies is an urgent need. Since the discovery in 2004 that a major proportion of T-ALL patients carry activating mutations that turn NOTCH1 into an oncogene, great efforts have been made to decipher the mechanisms underlying constitutive NOTCH1 activation, with the aim of understanding how NOTCH1 dysregulation converts the physiological NOTCH1-dependent T-cell developmental program into a pathological T-cell transformation process. Several molecular players have so far been shown to cooperate with NOTCH1 in this oncogenic process, and different therapeutic strategies have been developed to specifically target NOTCH1-dependent T-ALLs. Here, we comprehensively analyze the molecular bases of the cross-talk between NOTCH1 and cooperating partners critically involved in the generation and/or maintenance and progression of T-ALL and discuss novel opportunities and therapeutic approaches that current knowledge may open for future treatment of T-ALL patients.

show abstract

“…A research team identify oxidative phosphorylation as a critical pathway for leukaemia cell survival and demonstrate a direct relationship between notch receptor 1 and elevated oxidative phosphorylation gene expression. IACS‐010759, a mitochondrial complex I/oxidative phosphorylation inhibitor, has been investigated in clinical trials of acute myelocytic leukaemia and improved overall survival (NCT03291938 and NCT02882321) (Baran et al, 2022). An important study showing that presenilin 1 (PSEN1) selective inhibitor could be safer for treatment in T‐acute lymphoblastic leukaemia patients with NOTCH1 mutations.…”

Section: Adult T‐acute Lymphoblastic Leukaemia Targeted Therapymentioning

confidence: 99%

The pathogenesis and development of targeted drugs in acute T lymphoblastic leukaemia

Chen

Xin

Wei

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

Acute lymphoblastic leukaemia (ALL) is mainly classified into acute T-and Blymphoblastic leukaemia according to the source of its lymphocytes, thymus and bone. Among them, the incidence of adult T-cell accounts for about 25% of adult acute lymphoblastic leukaemia, but the degree of malignancy is high and the treatment rate and prognosis are poor. At this stage, there are few targeted drugs and the commonly used broad-spectrum chemotherapeutic drugs have poor efficacy and many adverse drug reactions. Understanding and investigating the pathogenesis of T-acute lymphoblastic leukaemia is very important for further developing new targeting drugs and improving existing drugs. Dysregulated signalling pathways are the main aetiological factors of T-acute lymphoblastic leukaemia. They play crucial roles in promoting tumour initiation, progression, drug design and therapy responses. This is primarily because signalling pathways are indispensable for many cellular biological processes, including tumour growth, migration, invasion, metastasis and others. As a result, small molecule inhibitors targeting the major kinase components of the signalling pathway have received a lot of attention and have been developed and evaluated in preclinical models and clinical trials. Already marketed drugs are also being repurposed in combination therapies to further improve efficacy and overcome tumour cell resistance. In this review, we have aimed to examine the latest and most classical signalling pathways in the aetiology of T-acute lymphoblastic leukaemia and shed light on potential targets for novel therapeutic agents to act on.

show abstract

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia

Cited by 34 publications

References 76 publications

Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia

Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T‐cell acute lymphoblastic leukemia

Notch Partners in the Long Journey of T-ALL Pathogenesis

The pathogenesis and development of targeted drugs in acute T lymphoblastic leukaemia

Contact Info

Product

Resources

About