bims-almceb 2021-12-26 papers

J Clin Med. 2021 Dec 11. pii: 5805. [Epub ahead of print]10(24):

Shedding Light on Targeting Chronic Myeloid Leukemia Stem Cells.

Mohammad Houshmand, Alireza Kazemi, Ali Anjam Najmedini, Muhammad Shahzad Ali, Valentina Gaidano, Alessandro Cignetti, Carmen Fava, Daniela Cilloni, Giuseppe Saglio, Paola Circosta.

Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts.

Keywords: bone marrow microenvironment; chronic myeloid leukemia; leukemia stem cells; treatment free remission

DOI: https://doi.org/10.3390/jcm10245805

Int J Cancer. 2021 Dec 18.

Microenvironment and drug resistance in acute myeloid leukemia: Do we know enough?

Saravanan Ganesan, Vikram Mathews, Neha Vyas.

Acute myeloid leukemia (AMLs), as the name suggests, often develop suddenly and are very progressive forms of cancer. Unlike in acute promyelocytic leukemia, a subtype of AML, the outcomes in most other AMLs remain poor. This is mainly attributed to the acquired drug resistance and lack of targeted therapy. Different studies across laboratories suggest that the cellular mechanisms to impart therapy resistance are often very dynamic and should be identified in a context-specific manner. Our review highlights the progress made so far in identifying the different cellular mechanisms of mutation-independent therapy resistance in AML. It reiterates that for more effective outcomes cancer therapies should acquire a more tailored approach where the protective interactions between the cancer cells and their niches are identified and targeted.

Keywords: AML; acute myeloid leukemia; drug resistance; miRNA; microenvironment; resistance

DOI: https://doi.org/10.1002/ijc.33908

Cancer Metastasis Rev. 2021 Dec 21.

Extracellular citrate and metabolic adaptations of cancer cells.

E Kenneth Parkinson, Jerzy Adamski, Grit Zahn, Andreas Gaumann, Fabian Flores-Borja, Christine Ziegler, Maria E Mycielska.

It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

Keywords: Cancer-associated cells; Citrate; OXPHOS; Redox; Senescence; Warburg effect

DOI: https://doi.org/10.1007/s10555-021-10007-1

J Leukoc Biol. 2021 Dec 20.

Bone marrow microenvironment drives AML cell OXPHOS addiction and AMPK inhibition to resist chemotherapy.

Ruolan You, Diyu Hou, Bin Wang, Jingru Liu, Xiaoting Wang, Qirong Xiao, Zhipeng Pan, Dongliang Li, Xiaoming Feng, Lixia Kang, Ping Chen, Huifang Huang.

The stromal niche plays a pivotal role in AML chemoresistance and energy metabolism reprogramming is a hallmark of a tumor. 5'-Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor suppressing mammalian target of rapamycin complex 1 (mTORC1) activity. However, the role of AMPK-mTORC1 pathway on connecting AML cell energy metabolism reprogramming and chemoresistance induced by the bone marrow microenvironment (BMM) is not defined. Here, with a co-culture system that simulates the interaction between BMM and AML cells, it is shown that stromal contact led to a decreased sensitivity to chemotherapy accompanied by an increase of oxidative phosphorylation (OXPHOS) activity and mitochondrial ATP synthesis in AML cells. The increased OXPHOS activity and excessive ATP production promoted chemoresistance of AML cells through inhibiting AMPK activity and in turn activating mTORC1 activity. In an in vivo AML mouse model, depletion of AMPK activity with genetic targeting promoted AML progression and reduced their sensitivity to chemotherapeutic drugs. Collectively, AML cells' acquired increased OXPHOS activity as well as AMPK inhibition could be therapeutically exploited in an effort to overcome BMM-mediated chemoresistance.

Keywords: AMPK-mTORC1 pathway; ATP; OXPHOS; acute myeloid leukemia; chemotherapy resistance

DOI: https://doi.org/10.1002/JLB.6A0821-409RR