There is no doubt that fasting weakens CML and it's important to keep taking TKI while fasting, which may be difficult for those on Imatinib. The question is how long we need to fast or perhaps how often. Maybe 3-4 days every other week or once a month would be as effective as 12+ days in a row. I fasted 87 hours between 11th and 15th, which is the first time since June 2024 when i started Asciminib. I'm trying again today and will keep pushing for more days and as often as I can. Maybe we can train ourselves into it just like people force themselves into gym and then eventually get hooked on and enjoy it.
The documentary explains that institutionalised fasting generally aims at 12 to 21 days. Since they have lots of experience with it, I assume they generally don't see effects under 12 days and see no significant benefits after 21 day. But every case is specific, e.g. in case of alzheimer they target protein clusters that form in the brain, and protein melts slowly as body uses only 5% of it while melting mostly fat. That would explain why such a problem may require longer fast, while CLL is affected by 72 hours fast as it depends on fatty acids.
5.4 Resistance of Leukaemia Stem Cells to TKI
LSCs in CML resist TKIs through both kinase-dependent and independent mechanisms. Kinase-dependent resistance occurs through BCR-ABL1 mutations, while kinase-independent resistance involves alternative survival pathways (e.g., Wnt/β-catenin, JAK/STAT), metabolic changes, epigenetic alterations, and protective interactions with the bone marrow microenvironment [88]. These mechanisms enable LSCs to evade TKI-induced apoptosis, contributing to disease persistence and relapse. Targeting these pathways and the bone marrow niche shows potential for addressing TKI resistance [89].
5.4.1 Role of Inflammatory Cytokines
In CML, LSC resistance to TKIs is facilitated by inflammatory cytokines. Cytokines, such as IL-6, TNF-α, TGF-β, and IL-1β, contribute to the survival, quiescence, and treatment resistance of LSCs through the activation of signaling pathways like JAK/STAT, NF-κB, and PI3K/Akt. IL-6 stimulates survival and growth through STAT3, and TNF-α triggers NF-κB to increase anti-apoptotic proteins, myeloid cell leukemia sequence 1 (MCL-1) and B-cell lymphoma 2 (BCL-2) [90]. TGF-β induces LSC quiescence, rendering them less susceptible to TKI therapy, and IL-1β fosters an inflammatory environment that enhances LSC resilience. Furthermore, these cytokines improve the adhesion of LSCs to the bone marrow niche, providing additional protection against TKI-induced apoptosis. Inhibiting these cytokine-driven pathways via JAK/STAT, TGF-β, and NF-κB inhibitors offers a promising approach to combat LSC resistance and enhance treatment outcomes in CML [91, 92].
5.4.2 Kinase-Independent Mechanism in Resistance
LSCs in CML exhibit kinase-independent resistance to TKIs, allowing them to persist despite effective inhibition of BCR-ABL1 activity. This resistance arises from the activation of alternative signaling pathways, such as Wnt/β-catenin, Hedgehog, PI3K/AKT, and JAK/STAT, which facilitate LSC survival and self-renewal. Additionally, LSCs undergo metabolic reprogramming, shifting towards oxidative phosphorylation to sustain energy production under TKI treatment. The BMM provides additional protection to LSCs through interactions facilitated by CXCR4/SDF-1 and N-cadherin, as well as through cytokine signaling [93]. Epigenetic alterations, including histone modifications and DNA methylation, can suppress genes that cause apoptosis and increase survival pathways. Additionally, LSCs frequently exist in a dormant state (G0 phase), making them less vulnerable to TKIs, which mainly affect cells that are actively dividing. Anti-apoptotic proteins such as MCL-1, BCL-2, and BCL-XL further enhance LSC resistance by blocking cell death induced by TKIs. Targeting these kinase-independent pathways with inhibitors of Wnt/β-catenin, JAK/STAT, and BCL-2, along with approaches that disrupt LSC-niche interactions and epigenetic regulators, offers a great therapeutic strategy to tackle TKI resistance and eliminate LSCs in CML [94, 95].
https://onlinelibrary.wiley.com/doi/10.1111/ejh.70110
What inflammatory cytokines on which cml depends are inhibited during extended fasting and how it affects cml lscs?
https://share.google/aimode/GPCbj8m7oVKo1qLYj
What signaling pathways on which cml depends are inhibited during extended fasting and how it affects cml lscs' ability to avoid apoptosis?
https://share.google/aimode/P8VtF4TfZVvZFIR0E
40 days fast experience
https://www.youtube.com/watch?v=lQap6qZYA_c&t=2770s
