A clinically relevant population of leukemic CD34+CD38− cells in acute myeloid leukemia

Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34+CD38− cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34+ subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34+CD38− cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34+CD38−ALDHint leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34+CD38− cells and identifies those AML cells associated with relapse.

Download Full-text

Minimal Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia

Leukemia ◽

10.5772/52080 ◽

2013 ◽

Cited By ~ 1

Author(s):

W. Zeijlemaker ◽

G.J. Schuurhuis

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Residual Disease ◽

Leukemic Stem Cells ◽

Minimal Residual ◽

Acute Myeloid

Download Full-text

Quantitative Assessment of Minimal Residual Disease Predicts Outcome of Patients of Acute Myeloid Leukemia with Nucleophosmin (NPM) Mutation.

Blood ◽

10.1182/blood.v108.11.561.561 ◽

2006 ◽

Vol 108 (11) ◽

pp. 561-561 ◽

Cited By ~ 4

Author(s):

Wen-Chien Chou ◽

Jih-luh Tang ◽

Shang-Ju Wu ◽

Ming Yao ◽

Hwei-Fang Tien

Keyword(s):

Acute Myeloid Leukemia ◽

Minimal Residual Disease ◽

Genomic Dna ◽

Myeloid Leukemia ◽

Residual Disease ◽

Prognostic Significance ◽

Clinical Relapse ◽

Minimal Residual ◽

Acute Myeloid

Abstract Purpose: In patients of acute myeloid leukemia (AML) with mutations in Nucleophosmin (NPM), minimal residual disease (MRD) can be quantified by real-time polymerase chain reaction (qPCR). However, the validity of MRD detection by qPCR on a long-term basis and its prognostic significance remain undetermined. Patients and Methods: We quantified NPM mutants by qPCR in genomic DNA of 202 bone marrow samples serially collected during a median follow-up of 21.9 months (range 2.5 to 204) from 40 AML patients bearing this mutation. Results: With a relatively homogeneous number of mutants at diagnosis, induction chemotherapy resulted in a median of 2.78 logs of reduction (p<0.001). The mutant numbers determined by qPCR matched well with clinical courses: clinical relapse was accompanied by rise of mutants (p<0.001) and mutant numbers at morphological complete remission from patients without any subsequent relapse were significantly lower than others (p<0.001). Detection of mutant signals predicted relapse if no further chemotherapy was administered. Failure to achieve at least 2 logs of mutant reduction after consolidation led to shorter overall survival (OS) (11.3 months vs. not reached, p=0.01) and relapse-free survival (RFS) (3.8 months vs. 21.2 months, p=0.001). Patients with any rise of mutants during serial follow-up relapsed more frequently than those with persistently low or undetectable signals (p<0.001). Along serial follow-up, patients obtaining any mutant reduction to < 0.1% of internal control (INC) after treatment had longer OS (a median of 57.9 months vs. 20.2 months, p=0.002) and RFS (11.3 months vs. 4.0 months, p<0.001). On the other hand, detection of mutants above 1.5% of INC in any post-induction sample predicted a poorer outcome (a median of 22.1 months vs. not reached, p=0.002 for OS and 9.7 months vs. not reached, p<0.001 for RFS). Conclusion: Quantification of MRD by qPCR on genomic DNA in AML bearing NPM mutation predicts outcomes of this group of patients.

Download Full-text