I am also curious about the preferred energy source of CLL cells.
Particularly the cholesterol role. If the CLL cells use cholesterol do they use whatever is present, or is there a signaling going on telling/initiating production—that causes cholesterol to rise?
Below are a few articles I found on the subject.
4. Serum Cholesterol Levels and Prognosis in CLL
Studies suggest that rates of dyslipidemia are higher among CLL patients than age-matched healthy controls [15]. One study showed that CLL patients suffer from hypercholesterolemia, observing elevated LDL levels in 75% of CLL patients [16]. Another study reported lower serum levels in CLL patients compared to healthy individuals, with CLL patients averaging 151.2 +/− 11.2 mg/dL compared to 195.3 +/− 8.5 mg/dL in healthy, aged-matched controls [17]. CLL patients with hypocholesterolemia have a shorter overall and treatment-free survival [18], possibly due to increased catabolism of LDL and impaired hepatic lipoprotein synthesis [17], or increased expression of the LDL receptor (LDLR) on CLL cells [19], leading to increased cellular uptake.
Hypercholesteremia may be due to an increase in the hepatic secretion of cholesterol into the blood stream; this may potentially fuel the rapid proliferation of leukemic cells in patients with a poor prognosis [20]. This notion is supported by a study that focused on patients with high-risk disease, defined by unmutated IGHV status (UM–IGHV). Using a metabolomic approach, significantly higher levels of serum cholesterol and LDL fatty acid side chains were observed in patients with high-risk disease [20]. This study also determined that UM–IGHV patients had higher levels of VLDL and lower levels of HDL cholesterol compared to patients with mutated IGHV genes (M–IGHV), while LDL levels were similar between the two groups of patients [20]. Hyperlipidemia may lead to inflammation, which helps drive CLL cell proliferation [21]. It is not surprising that statins, commonly used to treat hypercholesteremia, delayed the need for treatment by nearly 3 years [16].
In another study, no association between serum levels of LDL, HDL, total cholesterol and triglycerides, and clinical outcomes was observed [22]. However, this study included samples from a relatively small number of patients (n = 26), which raises the possibility that discrepancies between the studies may, at least in part, be due to the heterogeneity among CLL patients, and that much larger cohort studies are warranted. While there are conflicting reports concerning the role of cholesterol in CLL, there is clear evidence that cholesterol uptake and metabolism is disordered in CLL cells compared to healthy B-cells and other blood cancers, including acute lymphoblastic (ALL), acute myeloid (AML), and chronic myeloid leukemia (CML) [23].
frontiersin.org/journals/im...
Hematologic malignancies
Studies of the relationship between blood cholesterol levels and leukemia have yielded conflicting results. Lower cholesterol concentrations were reported in patients with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) than in healthy controls (108, 109), but a different report documented high cholesterol levels in patients with CLL (110). The results of another study demonstrated that in patients with CLL, elevated SREBP2 expression resulted in increased LDLR, thus cholesterol accumulation in the tumor cell cytoplasm was noted as a possible cause of this cancer (111).
sciencedirect.com/science/a...
Abstract
Low cholesterol levels may be accompanied by solid tumors or hematological malignancies such as multiple myeloma. Decreased cholesterol levels have been reported in some experimental studies about chronic lymphocytic leukemia (CLL). It may be associated with tumoral cell metabolism. Herein, we examine blood lipid profiles of patients with newly diagnosed CLL (284 male, 276 female, mean age 64 ± 11 years) as defined by National Cancer Institute criteria. The control group consisted of 71 healthy subjects with mean age 55 ± 9 years (28 male, 43 females). 60% of patients with Binet A, while 25% were Binet C. Decreased levels of total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) were observed in patients with CLL than control group (p < 0,001). There was no statistical significance between CLL and control group for triglycerides (TG) and very low density lipoprotein (VLDL), also between HDL-C, VLDL, TG and grades. Cholesterol may metabolized by abnormal lymphocytes in CLL patients.
aacrjournals.org/cebp/artic...
Discussion
In an a priori hypothesis-driven analysis, we found that use of low-potency lipophilic statins was associated with lower CLL risk, OR = 0.64 (95% CI, 0.45–0.92), with some indication of a dose–response effect. We did not detect a similar association with the use of either high-potency lipophilic statins or hydrophilic statins.
The association between statin use and CLL risk has been studied before. Using questionnaires to measure statin use, a study conducted in 6 European nations (including 410 patients with CLL) reported an OR of 0.83 (95% CI, 0.51–1.34) for all statins combined (16). A prospective U.S. cohort study found, based on biannual questionnaires, that cholesterol-lowering drugs (93% of which were statins) had a risk ratio of 1.01 (0.59–1.74) for former users, and 0.91 (0.66–1.27) and 0.85 (0.58–1.23) for current users for less and more than 5 years of use, respectively (17). The number of patients with CLL in this study was relatively small (326) with only 50 recent statin users and 49 long-term users; ref. 17). Our estimates for statin use as a class (OR = 0.89; 95% CI, 0.76–1.04) are in line with these results, despite differences in study design and data sources.
To the best of our knowledge, this is the first study to examine the association between low-potency lipophilic statins and CLL incidence (the analyses in the abovementioned studies were limited to studying the effects of statins as a class). Pharmacokinetic differences between lipophilic and hydrophilic statins may explain the differences in their association with CLL risk. The water solubility of statins affects their absorption and distribution in tissue (33, 34). Hydrophilic statins cannot easily penetrate cell plasma membranes through passive transport and their distribution is more hepatoselective (4, 35). However, this does not explain differences we observed between low-potency and high-potency lipophilic statins. The indications for individual statins are overlapping and clinical guidelines do not recommend certain types over others (36, 37), even though high-potency statins are prescribed when a larger reduction of low-density lipoprotein cholesterol (LDL-C) levels is desired (38). There is no clear connection between the type of statin and its effect on the MVA pathway in CLL cells. This remains an unexamined area as most animal and laboratory studies are limited to studying a specific statin (39).
Simvastatin has shown cytotoxicity against cultured B-CLL cells with higher levels of apoptosis with increased dosage (6). Fluvastatin showed higher cytotoxicity against lymphoma cells than atorvastatin and simvastatin (39). The statins have been shown to downregulate the anti-apoptotic protein BCL2 in some leukemias (40), and the complete remission rate in CLL is increased when simvastatin is combined with venetoclax, another agent that selectively reduces BCL2 levels in CLL cells (41, 42). Elevated LDL levels in CLL cells may decrease apoptosis of CLL cells; this was not observed for acute leukemia cells or normal lymphocytes (43).
Strengths and limitations
A major strength of this study is the availability of high-quality, population-based health administrative databases in Manitoba. The completeness and accuracy of the MCR and MH databases are well established (20, 21). We had a relatively large number of cases compared with other CLL studies, but some of our estimates were imprecise due to infrequent use of certain statins (especially low-potency lipophilic statins). Reporting of cancer cases to the MCR is mandated by provincial law (44). The MCR currently obtains data for all persons diagnosed with CLL cells using flow cytometry (but excludes cases with monoclonal B lymphocytosis). CLL incidence was underreported before reporting of flow cytometry became a standard practice (45). It is possible that some diagnosed cases during that time were not included in the MCR, this misclassification was likely nondifferential with respect to statin use.
A limitation of this study is that the DPIN database started in 1995. Statins prescribed before that time could not be identified. Statins were not, however, frequently prescribed before 1995 (46, 47) and have only been available since around 1990 (Supplementary Table S1). Also, any resulting misclassification is likely nondifferential with regard to the outcome (CLL diagnosis) as it excludes all exposure information before 1995. Although we adjusted our analysis for several confounding factors, we could not adjust for undiagnosed chronic cardiovascular disease. We also lacked information on aspirin use unless it was prescribed which is the likely the case for regular users. As a result, we cannot rule out residual confounding. We did not have information on some potential confounders, such as smoking, alcohol use and environmental exposures, albeit the literature suggests this does not cause significant confounding (2).
Although dyslipidemia has been associated with the development of CLL (48), the effect of the severity of dyslipidemia has not been studied. Our study is limited by a lack of data on cytokine and lipid levels; we could not stratify our analysis by severity of dyslipidemia. The low-potency statin users in our study used a relatively low dose of statins and were generally older and more likely to have chronic cardiovascular disease and other comorbidities. Confounding by indication may have biased our results if risk factors for CLL influenced statin prescriptions.
In summary, our results suggest that use of low-potency lipophilic statins might be associated with a lower risk of CLL, possibly in a dose-dependent manner. Even though a causal relationship cannot be proven, a 35% reduction in CLL risk is a promising, clinically relevant result that warrants further investigation into the effects of low-potency lipophilic statins on CLL risk.