Abstract
Acute myeloid leukemia (AML) is believed to arise from leukemic stem-like cells (LSC) making understanding the biological differences between LSC and normal stem cells (HSC) or common myeloid progenitors (CMP) crucial to understanding AML biology. To determine if protein expression patterns were different in LSC compared to other AML and CD34+ populations, we measured the expression of 121 proteins by Reverse Phase Protein Arrays (RPPA) in 5 purified fractions from AML marrow and blood samples: Bulk (CD3/CD19 depleted), CD34-, CD34+(CMP), CD34+CD38+ and CD34+CD38-(LSC). LSC protein expression differed markedly from Bulk (n=31 cases, 93/121 proteins) and CD34+ cells (n= 30 cases, 88/121 proteins) with 54 proteins being significantly different (31 higher, 23 lower) in LSC than in either Bulk or CD34+ cells. Sixty-seven proteins differed significantly between CD34+ and Bulk blasts (n=69 cases). Protein expression patterns in LSC and CD34+ differed markedly from normal CD34+ cells. LSC were distinct from CD34+ and Bulk cells by principal component and by protein signaling network analysis which confirmed individual protein analysis. Potential targetable submodules in LSC included the proteins PU.1(SP1), P27, Mcl1, HIF1α, cMET, P53, Yap, and phospho-Stats 1, 5 and 6. Protein expression and activation in LSC differs markedly from other blast populations suggesting that studies of AML biology should be performed in LSC.
Highlights
Acute Myelogenous Leukemia (AML) patients die of their disease when therapy fails to eradicate all the neoplastic cells, resulting in rapid or delayed regrowth of leukemic blasts
The discovery of leukemia stemlike cells (LSC) or initiating cells (LIC) generated the hypothesis that cells crucial for leukemia regrowth exist within the LSC pool rather than the bulk AML population[1]
Protein expression levels for all 121 antibodies were compared between the five different AML subsets including two intra-subset comparisons: CD34+ vs. CD34- and CD34+CD38+ vs. CD34+CD38- and three inter-subset comparisons: CD34+CD38- vs. CD34+, CD34+CD38- vs. Bulk and CD34+ vs. Bulk
Summary
Acute Myelogenous Leukemia (AML) patients die of their disease when therapy fails to eradicate all the neoplastic cells, resulting in rapid (primary refractory) or delayed (relapse) regrowth of leukemic blasts. The discovery of leukemia stemlike cells (LSC) or initiating cells (LIC) generated the hypothesis that cells crucial for leukemia regrowth exist within the LSC pool rather than the bulk AML population[1]. If this hypothesis is true, improving therapy for AML will depend on understanding how the biology of the chemoresistant LSC differs from the chemosensitive non-stem leukemic cells. LSC are further distinguished from normal HSC by characteristics within the side population by flow cytometry[5].
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