Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche

Ye, Haobin; Adane, Biniam; Khan, Nabilah; Sullivan, Timothy M.; Minhajuddin, Mohammad; Gasparetto, Maura; Stevens, Brett M.; Pei, Shanshan; Balys, Marlene; Ashton, John M.; Klemm, Dwight J.; Woolthuis, Carolien M.; Stranahan, Alec W.; Park, Christopher Y.; Jordan, Craig T.

doi:10.1016/j.stem.2016.06.001

Cited by 430 publications

(432 citation statements)

References 48 publications

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“…Another means of resistance has recently been reported by the Jordan laboratory, 115 which identified a specific subset of LSCs, in blast crisis CML and AML, that were able to highjack the lipolytic process in gonadal adipose tissue to fuel their metabolic needs and evade chemotherapy-induced apoptosis. These cells expressed the fatty acid transporter, CD36.…”

Section: Metabolic Adaptationmentioning

confidence: 99%

“…131 Functionally, transplantation of young HSCs to aged recipients results in reduced homing and engraftment, increased myeloid output, and a shift toward reduced clonality. 132,133 Conversely, exposure of aged HSCs to a young environment reduces Approaches to prevent or overcome therapeutic resistance include the inhibition of the FAO by blocking the function of the rate-limiting enzyme CPT-1 (eg, etomoxir, ranolazine), 115 or interfering with mitochondrial function using tigecycline.…”

Section: Relevance Of Age-related Niche Changes To Myeloid Malignanciesmentioning

confidence: 99%

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The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

Medyouf

2017

Blood

106

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Similar to their healthy counterpart, malignant hematopoietic stem cells in myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia, reside in a highly complex and dynamic cellular microenvironment in the bone marrow. This environment provides key regulatory signals for and tightly controls cardinal features of hematopoietic stem cells (HSCs), including self-renewal, quiescence, differentiation, and migration. These features are essential to maintaining cellular homeostasis and blood regeneration throughout life. A large number of studies have extensively addressed the composition of the bone marrow niche in mouse models, as well as the cellular and molecular communication modalities at play under both normal and pathogenic situations. Although instrumental to interrogating the complex composition of the HSC niche and dissecting the niche remodeling processes that appear to actively contribute to leukemogenesis, these models may not fully recapitulate the human system due to immunophenotypic, architectural, and functional inter-species variability. This review summarizes several aspects related to the human hematopoietic niche: (1) its anatomical structure, composition, and function in normal hematopoiesis; (2) its alteration and functional relevance in the context of chronic and acute myeloid malignancies; (3) age-related niche changes and their suspected impact on hematopoiesis; (4) ongoing efforts to develop new models to study niche-leukemic cell interaction in human myeloid malignancies; and finally, (5) how the knowledge gained into leukemic stem cell (LSC) niche dependencies might be exploited to devise novel therapeutic strategies that aim at disrupting essential niche-LSC interactions or improve the regenerative ability of the disease-associated hematopoietic niche.

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Section: Metabolic Adaptationmentioning

confidence: 99%

Section: Relevance Of Age-related Niche Changes To Myeloid Malignanciesmentioning

confidence: 99%

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

Medyouf

2017

Blood

106

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“…The FA transporter CD36 is reportedly a marker of poor prognosis in AML [42]. FAO is activated in a subset of leukemia cells, especially in leukemia stem cells (LSCs) residing in gonadal adipose tissue, compared to normal blood cells [43]. These LSCs highly express the FA transporter CD36 and activate lipolysis in gonadal adipose tissue, a metabolic adaptation that protects LSCs from chemotherapy.…”

Section: Adipocytes Fatty Acid Metabolism and Hematopoiesismentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…+ cells are more resistant to chemotherapeutics [63]. Taken together, these illustrate the role the leukemic microenvironment plays in LSCs maintenance and drug resistance.…”

Section: Lscs Crosstalk With the Microenvironmentmentioning

confidence: 78%

“…During treatment, LSCs 'home' to adipose tissue to escape detection [63]. The adipose niche induces a pro-inflammatory response from the LSCs.…”

Section: Lscs Crosstalk With the Microenvironmentmentioning

confidence: 99%

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

et al. 2017

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Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche

Cited by 430 publications

References 48 publications

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

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