Page 120 - Haematologica Vol. 110 - January 2025

ARTICLE - LIPA modulates venetoclax/TKI response in bpCML A
M. Minhajuddin et al.
Figure 6. Venetoclax/dasat- inib treatment results in an increase of free fatty acids in leukemia stem cells. (A) Experimental design for treatment followed by me- tabolomic analysis of free fatty acids in leukemia stem cells. (B) Relative amounts of different fatty acids in leukemia stem cells in re- sponse to treatment with a-linolenic acid, myristoleic acid, hexadecanoic acid or dihomo-g-linolenic acid. (C, D) Leukemia cells (GY+, lin–) were pre-treated in vitro with linolenic acid (10 μM) (C) or dihomo-g-linolenic ac- id (10 μM) (D) for 1 h and then treated for 24 h with the venetoclax/dasatinib com- bination (100 nM). Viability was measured compared to vehicle control. Error bars denote mean ± standard de- viation from triplicate exper- iments. Statistical analyses were performed using a Stu- dent t test. NS: not statisti- cally significant, *P≤0.05, ***P≤0.001, ****P≤0.0001. LSC: leukemia stem cells: Ven/Dasa: venetoclax and dasatinib combination; AU: arbitrary units; LA: linolenic acid; DGLA: dihomo-g-lino- lenic acid.
B
CD
primary human bpCML samples as well as in a previously described mouse model of bpCML. Survival experiments showed that the ven/dasa combination effectively cured mice of leukemia induced with wild-type Bcr-Abl, where- as untreated mice typically succumbed to disease within 10-15 days. We also showed the efficacy of venetoclax and ponatinib in a newly created mouse model harboring T315I mutant Bcr-Abl in combination with Nup98/HoxA9. Although we observed a significant survival benefit of ven/pona in the T315I mutant GY mouse model we were unable to determine
curative outcome due to the toxicity of ponatinib. Lower ponatinib doses in combination with venetoclax may allow eradication of LSC without treatment-related mortality. Our data further identify a compensatory upregulation of genes associated with lysosome biology upon treatment with ven/dasa. The functional relevance of this finding is clearly evident upon addition of bafilomycin to the ven/ dasa regimen, which significantly increased eradication of primitive bpCML cells. In particular, upregulation of LIPA seems to be a protective mechanism activated by these
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