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Blood, Vol. 109, Issue 6, 2589-2596, March 15, 2007
Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53
Blood Irish et al.
109: 2589
Supplemental materials for: Irish et al, Vol 109, Issue 6, 2589-2497
Files in this Data Supplement:
- Figure S1. Individual node maps for correlations based on Table S3 (PDF, 57.9 KB) -
Nodes representing p53 phosphorylation (at S15, S20, S37, S46, and S392), p53 expression, and Bcl-2 expression in AML patients were drawn at distances based on the linear correlation of these biomarkers in 30 AML patients (refer to Tables S1 and S3). The pixel length of the line is (1−r2) and is solid where r2 was greater than 0.6 (highly correlated), dashed where r2 was between 0.35 and 0.6, and widely dashed where r2 was less than 0.35. These maps for individual parameters were used as an intermediate prior to mapping the relationship between the set of parameters shown in Figure 6A.
- Figure S2. p53 phosphorylation at serine 20 was lower than normal in AML blast cells, did not correlate with Bcl-2 level, and was especially low in the FLT3-LM-SPY591 group (PDF, 101 KB) -
As described in Figure 5A, p53 phosphorylation on serine 20 (p-p53-S20) and Bcl-2 protein expression were measured in individual AML blast cells from 30 patients. A representative subset of AML patients and normal PBMCs are shown here. AML patients are arranged according to FLT3 mutational status.
- Figure S3. Greater than normal p53 phosphorylation at serine 37 was observed in all AML patient samples (PDF, 95.3 KB) -
As described in Figure 5A, p53 phosphorylation on serine 37 (p-p53-S37) and Bcl-2 protein expression were measured in individual AML blast cells from 30 patients. A representative subset of AML patients and normal PBMCs are shown here. AML patients are arranged according to FLT3 mutational status.
- Figure S4. p53 phosphorylation at serine 46 was comparable to serine 15 phosphorylation (PDF, 93.1 KB) -
As described in Figure 5A, p53 phosphorylation on serine 46 (p-p53-S46) and Bcl-2 protein expression were measured in individual AML blast cells from 30 patients. A representative subset of AML patients and normal PBMCs are shown here. AML patients are arranged according to FLT3 mutational status.
- Figure S5. p53 phosphorylation at serine 392 was lower than normal in most AML samples with FLT3-LM-SPY591 (PDF, 99.5 KB) -
As described in Figure 5A, p53 phosphorylation on serine 392 (p-p53-S392) and Bcl-2 protein expression were measured in individual AML blast cells from 30 patients. A representative subset of AML patients and normal PBMCs are shown here. AML patients are arranged according to FLT3 mutational status.
- Figure S6. p53 was often expressed at higher than normal levels in AML blasts (PDF, 92 KB) -
As described in Figure 5A, p53 protein expression (p53) and Bcl-2 protein expression were measured in individual AML blast cells from 30 patients. A representative subset of AML patients and normal PBMCs are shown here. AML patients are arranged according to FLT3 mutational status.
- Figure S7. Design of therapy to disrupt antiapoptotic signaling and activate p53 (PDF, 102 KB) -
Idarubicin, given in the standard course one of AML chemotherapy, causes DNA damage and leads to accumulation of phosphorylated wild-type p53 in AML blast cells. High levels of p53 activity normally lead to a program of arrest or apoptosis driven by p53 effectors, such as Bax and Bak. However, AML blast cells have aberrant STAT and MAPK family signaling transduction1 and signaling associated with the FLT3 mutation drives overexpression of Bcl-2, thereby blocking apoptosis. Based on these results, we suggest that AML chemotherapy could be improved using a three-tiered strategy that would include: (1) inhibition of the signaling mechanisms known to drive proliferation and Bcl-2 family member expression (eg, kinase inhibitors KIs), (2) inhibition of Bcl-2 family member activity (eg, BH3 mimic HA14-1), and (3) induction of DNA damage and activation of wild-type p53 using standard anthracycline-based chemotherapy (eg, idarubicin Ida).
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