Abstract 1556

P110α, β, γ and δ isoforms are catalytic domains of phosphoinosityl-3-kinase (PI-3K) which is frequently constitutively active in blast cells from acute myeloid leukemia (AML) patients. RNA and protein from all 4 isoforms were ubiquitously expressed in 32 AML samples which also showed expression of p-Akt Ser473, indicating PI-3K activation. Treatment of AML patient blast cells (n=45) with the p110α selective inhibitor PI3-Kinase alpha inhibitor 2 and p110δ selective inhibitor PCN5603 (Piramed Pharma,UK) caused dose dependent kill of AML colony forming cells (CFC) and inhibition of p-Akt Ser473 expression. In contrast, the P110β and p110γ selective inhibitors TGX-221 and AS-604850 showed little AML CFC kill. AML samples were more sensitive to PI3-Kinase alpha inhibitor 2 and PCN5603 killing than normal bone marrow or normal peripheral blood (Median IC50=1.8μM for 45 AML-CFC and 4.3μM for 8 normal CFC for PI3-Kinase alpha inhibitor 2. Median IC50=1.9μM for 45 AML-CFC and 6.2μM for 10 normal CFC for PCN5603). There was no significant difference between the IC50 and IC90 of p110α and δ inhibitors against AML CFC from samples with or without the FLT3 ITD. There was a weak correlation between the IC50 of the PI3-Kinase alpha inhibitor 2 or the IC50 of PCN5603 and the ratio of pAkt/total Akt (R2 = 0.23 and 0.24, respectively, p<0.05). RNAi inhibition of p110α and p110δ decreased the corresponding isoform's RNA and protein expression and caused AML CFC kill and inhibition of p-Akt Ser473 expression. There was a strong correlation between the percent AML CFC kill and RNA knockdown (R2 = 0.67) and between inhibition of p-Akt and p110 protein expression (R2 = 0.90 for α and 0.82 for δ). Thus, p110α and δ inhibition may achieve selective targeting of malignant rather than normal CFCs. Furthermore, treatment of AML cells with PCN5603, decreased survival of AML long-term culture- initiating cells (AML LTC-IC). In contrast, less toxicity toward normal bone marrow LTC-IC was observed (IC50=0.08μM, ≤2μM and 1.33μM for 3 AML samples and IC50=3.09μM, 2.63μM, >10μM and >10μM for 4 normal bone marrows). Selective inhibition of p110α and δ isforms of PI-3K kills AML progenitors including candidate leukemic stem cells (AML LTC-IC) with relative sparing of analogous normal cells suggesting that these molecules could be therapeutic targets in AML.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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