In addition, BCR-ABL1 induces upregulation of Bcl-2 anti-apoptotic proteins, including Mcl-1 and B-cell lymphoma-extra large (Bcl-xL) [8,18,128]

In addition, BCR-ABL1 induces upregulation of Bcl-2 anti-apoptotic proteins, including Mcl-1 and B-cell lymphoma-extra large (Bcl-xL) [8,18,128]. leading to proliferation of more than one cell lineage, with transitional forms from one entity to another. Over 95% of PV, ET, and PMF are associated with mutually exclusive somatic driver mutations 0.05) and oxidative stress via IP3 receptor inhibition (IP3R) on the endoplasmic reticulum (ER) [39,40,42]. Herrmann et al. demonstrated a decrease in CD26+ stem cells after in vitro IM therapy [16], yet Willmann et al. showed otherwise [36]. Moreover, nilotinib induced CML stem cell apoptosis [36], and nilotinib and dasatinib showed higher potency in IP3R inhibition [42]. IM may also downregulate overexpressed EZH2 in CML stem cells, with minimal effects in normal HSCs [17,43]. Also, in-vitro studies showed that post-dasatinib or -IM therapy, programmed death receptor 1 (PD-1, immune marker for immune-evasion) expression was found to be reduced on CD8+ T cells and monocytic myeloid-derived suppressor cells (MDSCs), leading to increased cytotoxic T-lymphocyte- (CTL) and Natural Killer (NK) cell-mediated cytotoxicity [18,44,45,46]. However, contradicting evidence was presented in another in vitro study, which showed that IM enhanced mRNA and protein expression of autophagy-related 4B cysteine peptidase (Atg4B), resulting in TKI-induced autophagy and selective Sutezolid survival in CD34+ CML cells ( 0.05) [39]. 2.2. Ponatinib Ponatinib, a third generation TKI, is indicated in CML with chimerism at 28 days was achieved compared to 50% in dasatinib and IM [22,47,50]. 2.3. Asciminib Asciminib (ABL001), a recent, FDA-approved, fourth generation TKI, is an allosteric inhibitor that binds to the BCR-ABL1 myristoyl-pocket (STAMP) [8,33,49,51,52]. It is effective against KD-dependent and -independent mutations as monotherapy or in combination with other TKIs to restore TKI-sensitivity in resistant cell lines and produce drug synergism in reducing CRK-like protein (CRKL) phosphorylation for CML stem cells [49,53]. Initial results in a phase I trial (ClinicalTrials.gov number, “type”:”clinical-trial”,”attrs”:”text”:”NCT03595917″,”term_id”:”NCT03595917″NCT03595917) demonstrated that 82% of patients with TKI-resistance achieved major cytogenetic response (MCyR) by 3 months and 30% of patients reached CCyR at 5 months [51]. In the phase III ASCEBEL trial, asciminib showed superiority over bosutinib in achieving MMR at 24 weeks [53]. Ongoing trials using asciminib as monotherapy, in combination with other TKIs and/or corticosteroids are underway (ClinicalTrials.gov identifiers: “type”:”clinical-trial”,”attrs”:”text”:”NCT04216563″,”term_id”:”NCT04216563″NCT04216563, “type”:”clinical-trial”,”attrs”:”text”:”NCT03906292″,”term_id”:”NCT03906292″NCT03906292, “type”:”clinical-trial”,”attrs”:”text”:”NCT04360005″,”term_id”:”NCT04360005″NCT04360005, “type”:”clinical-trial”,”attrs”:”text”:”NCT03106779″,”term_id”:”NCT03106779″NCT03106779, “type”:”clinical-trial”,”attrs”:”text”:”NCT03595917″,”term_id”:”NCT03595917″NCT03595917, “type”:”clinical-trial”,”attrs”:”text”:”NCT03578367″,”term_id”:”NCT03578367″NCT03578367 and “type”:”clinical-trial”,”attrs”:”text”:”NCT02081378″,”term_id”:”NCT02081378″NCT02081378). 2.4. Interferon- IFN was used as first-line treatment before the emergence Sutezolid of TKIs. It induces apoptosis of LSCs via Fas-receptors upregulation, FADD/caspase-8 pathway activation, and cytochrome-c release, leading to mitochondrial disruption and cellular apoptosis independent of anti-apoptotic B-cell lymphoma 2 (Bcl-2), cell-cycle arrest and tumour-suppressor p53 [54,55,56]. IFN also restores normal function of the dysregulated BMM through 1-integrin for cellular Sutezolid differentiation and elimination of the protective barrier established for LSC quiescence [54,57,58]. IFN–mediated increase in expression of major histocompatibility complex (MHC) class I molecules and tumour-associated antigens cause reactivation of CTL and prompt CTL-mediated cytotoxicity against LSCs [54,55]. The 5-year survival rate of IFN was 57% as Sutezolid shown in a meta-analysis of 7 data sets of randomized trials consisting of 1,554 patients [54,59]. In another study using IFN monotherapy, Sutezolid the 10-year survival rate was 72%, where 46% remained in CCyR [55,60]. These highlight the potential PT141 Acetate/ Bremelanotide Acetate re-emergence of IFN for LSC elimination, where clinical trials using IFN alone or in combination with other TKIs showed promising results for TFR (ClinicalTrials.gov identifiers: “type”:”clinical-trial”,”attrs”:”text”:”NCT02001818″,”term_id”:”NCT02001818″NCT02001818, “type”:”clinical-trial”,”attrs”:”text”:”NCT01657604″,”term_id”:”NCT01657604″NCT01657604, “type”:”clinical-trial”,”attrs”:”text”:”NCT03117816″,”term_id”:”NCT03117816″NCT03117816, “type”:”clinical-trial”,”attrs”:”text”:”NCT03831776″,”term_id”:”NCT03831776″NCT03831776, “type”:”clinical-trial”,”attrs”:”text”:”NCT04126681″,”term_id”:”NCT04126681″NCT04126681, “type”:”clinical-trial”,”attrs”:”text”:”NCT01316250″,”term_id”:”NCT01316250″NCT01316250, “type”:”clinical-trial”,”attrs”:”text”:”NCT02381379″,”term_id”:”NCT02381379″NCT02381379, and “type”:”clinical-trial”,”attrs”:”text”:”NCT00452023″,”term_id”:”NCT00452023″NCT00452023). 3. Current Therapeutic Options in MPN and Their Effects on MPN Stem Cells 3.1. IFN A major significance of Peg-IFN-2a is its ability to target MPN stem cells and reduce mutant allele burden in MPN [61,62,63,64,65,66,67,68]. Sustained molecular, haematological response and regression of BM fibrosis were seen in some patients after discontinuation of Peg-IFN-2a, indicating the eradication of MPN stem cells [65,69] (Table 2). Interestingly, the effect of Peg-IFN-2a on mutations in MPN. Table 2 Targeting of 0.05). Faster response in homozygous to mutation, which accounts for 90% in intermediate-2 and high-risk MF patients, is found to be associated with higher relapse risks [88]. In a study assessing the outcome of allo-HSCT in MPL-mutated PMF and secondary myelofibrosis (SMF), the only relapsed.