Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Abstract

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Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

“…Another study compared the global metabolic differences between murine HSC and CML stem cells, finding that CML stem cells accumulate significantly higher amounts of certain dipeptide species, which, when internalized, can activate p38MAPK and Smad3, regulating amino acid signaling and CML stemness. Pharmacological inhibition of the uptake of dipeptides compromised CML stem cell activity by targeting Smad3 signaling [ 131 ].…”

Druggable Biochemical Pathways and Potential Therapeutic Alternatives to Target Leukemic Stem Cells and Eliminate the Residual Disease in Chronic Myeloid Leukemia

“…Similarly, the BCL2/Bcl-xL inhibitor ABT-737 associated with Imatinib demonstrated strong synergism to induce cell death of both proliferating and quiescent CD34 + /CD38 − TKI-insensitive CML cell populations [22,23]. In two other studies, a cell death response was triggered on primary CML CD34 + quiescent cells by a triple combination associating ABT-737 to block BCL2 and Bcl-xL, Nilotinib to inhibit BCR-ABL and a MDM2 inhibitor such as Nutlin3a [24] or DS-5272 [25] to restore p53 activation.…”

“…Interestingly, BCL2 inhibition was demonstrated to reduce oxidative phosphorylation and selectively eradicate in AML-LSCs [186]. The previously described efficacy of BCL2 inhibition [25] in CML could be partially explained by this mechanism.…”

Killing the minotaur in its amazing maze

“…6 Similar MRD-tailored treatment concepts in the frontline and relapsed setting have been introduced also by other research groups. 7,8 The better and more sensitive our MRD detection tool is, the better and more precise our treatment strategy will be for the individual patient with CLL. NGS-based MRD assessment is currently also developed for molecular monitoring of other leukemias (eg, chronic myeloid leukemia).…”

“…5 Follow-up studies have shed light on other pathways and strategies for increasing levels of p53 to efficiently eradicate LSCs in CML. 6,7 Indeed, p53-activating agents may be an effective way of inducing cure in CML patients. 8 In the article by Park et al, the authors reveal a novel pathway that leads to decreased survival and self-renewal in CML via activation of p53 and depletion of c-Myc.…”