Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi-Numb signaling axis4,5. Specifically, we find that chronic phase is marked by high and blast crisis phase by low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced phase disease in vivo. As a possible explanation for the decreased levels of Numb in blast crisis, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML6,7, can trigger expression of the RNA binding protein Musashi2 (Msi2) which in turn represses Numb. Importantly, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for therapy of aggressive leukemias.
Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, upfront resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profi le, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these fi ndings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
The sesquiterpene lactone parthenolide has recently attracted
considerable attention owing to its promising antitumor properties, in
particular in the context of stem-cell cancers including leukemia. Yet, the lack
of viable synthetic routes for reelaborating this complex natural product have
represented a fundamental obstacle toward further optimization of its
pharmacological properties. Here, we demonstrate how this challenge could be
addressed via selective, late-stage sp3C—H
bond functionalization mediated by P450 catalysts with tailored
site-selectivity. Taking advantage of our recently introduced tools for
high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity
prediction, we evolved P450 variants useful for carrying out the highly
regioselective hydroxylation of two aliphatic sites (C9and C14) in parthenolide
carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and
C14-modified parthenolide analogs were generated in order to gain initial
structure-activity insights on these previously inaccessible sites of the
molecule. Notably, some of these compounds were found to possess significantly
improved antileukemic potency against primary acute myeloid leukemia cells,
while exhibiting low toxicity against normal mature and progenitor hematopoietic
cells. By identifying two ‘hot spots’ for improving the anticancer
properties of parthenolide, this study highlights the potential of P450-mediated
C—H functionalization as an enabling, new strategy for the late stage
manipulation of bioactive natural product scaffolds.
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