Variability in responsiveness to lovastatin of the primitive CD34+ AML subfraction compared to normal CD34+ cells

Jonge-Peeters, Susan D. P. W. M. de; Weide, Karen van der; Kuipers, Folkert; Sluiter, Wim J.; Vries, Elisabeth G.E. de; Vellenga, Edo

doi:10.1007/s00277-008-0633-2

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…Lovastatin was also shown to dampen in a heterogenous manner the primitive subfraction of CD34 + AML cells. 39 CD34 + AML cells that poorly responded in vitro identified a subgroup of AML patients with poor prognosis. 39 …”

Section: Manipulating Cholesterol Homeostasis In Hematopoietic Malign...mentioning

confidence: 99%

Targeting cholesterol homeostasis in hematopoietic malignancies

Brendolan¹,

Russo

2022

Blood

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Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.

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Section: Manipulating Cholesterol Homeostasis In Hematopoietic Malign...mentioning

confidence: 99%

Targeting cholesterol homeostasis in hematopoietic malignancies

Brendolan¹,

Russo

2022

Blood

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“…The effect of statins on AML cell survival has been predominantly studied using AML cell lines that do not completely recapitulate the disease and that poorly reflect the genetic heterogeneity of AML. Studies exploring the impact of statins on primary AML cells show a heterogeneity of responses 5,6 and a possible association between poor prognosis and reduced statin sensitivity 5 . To improve AML treatment outcome, addition of pravastatin to standard induction chemotherapy has been explored, and results of a phase I study were encouraging 7 .…”

Section: Introductionmentioning

confidence: 99%

“…Studies exploring the impact of statins on primary AML cells show a heterogeneity of responses 5,6 and a possible association between poor prognosis and reduced statin sensitivity. 5 To improve AML treatment outcomes, addition of pravastatin to standard induction chemotherapy has been explored, and results of a phase 1 study are encouraging. 7 A phase 2 study of idarubicin and cytarabine in combination with pravastatin reported an increased complete response rate for relapsed AML 8 and improved outcomes for patients with unfavorable prognosis.…”

Section: Introductionmentioning

confidence: 99%

Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia

et al. 2022

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Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML.

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“…AML is considered to be initiated by unchecked growth of immature cells as a result of accumulated mutations. Recent studies suggest that leukemic cells are heterogenous and their biological functions are diverse among the population [13]- [16]. For example, AML CD34 + cells exhibited more resistance to apoptosis than CD34fractions [13].…”

Section: Introductionmentioning

confidence: 99%

“…CD34 + CD38leukemia progenitors had increased chemotherapy resistance, decreased immunogenicity and dendritic cell transformation capacities compared to CD34 + CD38 + cells [15]. The primitive CD34 + cells displayed higher sensitivity to the cholesterol synthesis inhibitor lovastatin than CD34cells [16]. However, the underlying mechanisms are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the micromechanical properties of myeloblasts from cancer patients with optical tweezers

Tan

Leung

Wang

et al. 2010

2010 IEEE International Conference on Nano/Molecular Medicine and Engineering

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Cell mechanics, in particular mechanical properties, has been suggested as a new biomarker indicative of cell state and phenotype. Acute myeloid leukemia (AML) is characterized by the abnormal increase of myeloblasts in blood and bone marrow. While AML has been extensively studied from the perspectives of biochemical and genetic aspects, little is known about its cellular biophysical properties. In this study, optical tweezer technology was used to examine the micromechanical properties of myeloblasts from bone marrow of AML patients at single cell level. The myeloblasts were separately analyzed according to their expression of CD34 + , a marker of primitive hematopoietic cells. To extract the intrinsic properties from the relationship between the stretching force and the induced deformation, a theoretical approach was developed to model the mechanical responses of cells and further characterize their mechanical properties. The preliminary results show that the area compressibility modulus of CD34 + myeloblasts was significantly less than that of CD34cells, which indicate that micromechanical properties are unique features of myeloblasts and provide us with an insight into the cell mechanics of primitive AML cells.

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Variability in responsiveness to lovastatin of the primitive CD34+ AML subfraction compared to normal CD34+ cells

Cited by 14 publications

References 22 publications

Targeting cholesterol homeostasis in hematopoietic malignancies

Targeting cholesterol homeostasis in hematopoietic malignancies

Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia

Characterizing the micromechanical properties of myeloblasts from cancer patients with optical tweezers

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