High Stem Cell Frequency in Acute Myeloid Leukemia at Diagnosis Predicts High Minimal Residual Disease and Poor Survival
2005
Purpose: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event origi- nates from the CD34 + CD38 stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse.Therefore, the prognos- tic impact of stem cell frequency in CD34-positive AML was investigated. Experimental Design: First, the leukemogenic potential of unpurified CD34 + CD38 cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34 + CD38 compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients. Results: In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe com- bined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34 + CD38 stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34 + percentage showed no such correlations. Conclusions: Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34 + CD38 population at diagnosis reflects a higher percentage of chemotherapy- resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ulti- mately, future therapies should be directed toward malignant stem cells.
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