Prospective validation of the prognostic relevance of CD34+CD38- AML stem cell frequency in the HOVON-SAKK132 trial.
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SUBMITTER: Ngai LL
PROVIDER: S-EPMC10646801 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Prospective validation of the prognostic relevance of CD34+CD38- AML stem cell frequency in the HOVON-SAKK132 trial.
Ngai Lok Lam LL Hanekamp Diana D Janssen Fleur F Carbaat-Ham Jannemieke J Hofland Maaike A M A MAMA Fayed Mona M H E MMHE Kelder Angèle A Oudshoorn-van Marsbergen Laura L Scholten Willemijn J WJ Snel Alexander N AN Bachas Costa C Tettero Jesse M JM Breems Dimitri A DA Fischer Thomas T Gjertsen Bjørn T BT Griškevičius Laimonas L Juliusson Gunnar G van de Loosdrecht Arjan A AA Maertens Johan A JA Manz Markus G MG Pabst Thomas T Passweg Jakob R JR Porkka Kimmo K Valk Peter J M PJM Gradowska Patrycja P Löwenberg Bob B de Leeuw David C DC Janssen Jeroen J W M JJWM Ossenkoppele Gert J GJ Cloos Jacqueline J
Blood 20230501 21
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Project description:Patients with Fanconi anemia (FA) have a high risk of developing acute myeloid leukemia (AML). In this study, we attempted to identify cell-surface markers for leukemia-initiating cells in FA-AML patients. We found that the IL-3 receptor-? (IL-3R?) is a promising candidate as an leukemia-initiating cell-specific antigen for FA-AML. Whereas IL-3R? expression is undetectable on normal CD34(+)CD38(-) HSCs, it is overexpressed on CD34(+)CD38(-) cells from FA patients with AML. We examined the leukemia-initiating cell activity of IL-3R?-positive FA-AML cells in a "humanized" FA xenotransplant model in which we separated AML cells into IL-3R?-positive and IL-3R?-negative CD34 fractions and transplanted them into irradiated recipient mice. In all 3 FA-AML samples, only IL-3R?-positive cells showed significant levels of engraftment and developed leukemia in the recipient mice. The FA CD34(+)IL-3R?(+) blasts isolated from leukemic mice exhibited hypersensitivity to IL-3 deprivation and JAK2-STAT5 overactivation after IL-3 treatment. Finally, treatment of FA CD34(+)IL-3R?(+) blasts with an IL-3R?-neutralizing antibody inhibited IL-3-mediated proliferation and STAT5 activation. These results demonstrate that IL-3R? is a cell-surface marker present on FA-AML leukemia-initiating cells and may be a valuable therapeutic target.
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Project description:Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34+/CD38- LSCs in patients with Ph+ ALL (n = 22) and Ph- ALL (n = 27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41 = 24%), CD22 (12/20 = 60%), CD33 (Siglec-3) (20/48 = 42%), CD52 (CAMPATH-1) (17/40 = 43%), IL-1RAP (13/29 = 45%), and/or CD135 (FLT3) (4/20 = 20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph+ ALL exhibiting BCR/ABL1p210, whereas in Ph+ ALL with BCR/ABL1p190, LSCs variably expressed CD25 but did not express CD26. In Ph- ALL, CD34+/CD38- LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34+/CD38- and CD34+/CD38+ cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph+ and Ph- ALL display unique marker- and target expression profiles. In Ph+ ALL with BCR/ABL1p210, the LSC-phenotype closely resembles the marker-profile of CD34+/CD38- LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.
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Project description: Not available
2008-08-01 | E-NCMF-11 | biostudies-arrayexpress
Project description:Lin-, CD38-, CD34+ hematopoietic stem cells. Keywords: other
2005-12-09 | GSE3788 | GEO
Project description:Gene expression profiles of CD34+CD38- stem cells and more differentiated CD34+CD38+ progenitor cells were compared. Comparison of expression profiles of hematopoietic stem cells from fetal liver, umbilical cord blood, bone marrow and mobilized pheripheral blood allowed us to identify a unique set of genes with conserved expression during ontogeny. Keywords: Cell type comparison
2008-09-10 | GSE6146 | GEO
Project description:AimTo evaluate quantitatively and qualitatively the different CD34(+) cell subsets after priming by chemotherapy granulocyte colony-stimulating factor (± G-CSF) in patients with acute myeloid leukemia.MethodsPeripheral blood and bone marrow samples were harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4 (CXCR4) (CD184), VLA-4 (CD49d/CD29) and CD47.ResultsChemotherapy ± G-CSF mobilized immature cells (CD34(+)CD38(-) population), while the more mature cells (CD34(+)CD38(low) and CD34(+)CD38(+) populations) decreased progressively after treatment. Circulating CD34(+) cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34(+) cell mobilization was correlated with a gradual increase in CXCR4 and CD47 expression, suggesting a role in cell protection and the capacity of homing back to the marrow.ConclusionChemotherapy ± G-CSF mobilizes into the circulation CD34(+) bone marrow cells, of which, the immature CD34(+)CD38(-) cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients' outcomes.
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Project description:The prognostic impact of immunophenotypic CD34+CD38-CD123+ leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34+CD38-CD123+ iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) (p <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% (p = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents.
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Project description:Gene expression profiles of CD34+CD38- stem cells and more differentiated CD34+CD38+ progenitor cells were compared. Comparison of expression profiles of hematopoietic stem cells from fetal liver, umbilical cord blood, bone marrow and mobilized pheripheral blood allowed us to identify a unique set of genes with conserved expression during ontogeny. Experiment Overall Design: CD34+CD38- en CD34+CD38+ cell populations were isolated by cell sorting from human Bone Marrow, mobilized peripheral blood, umbilical cord blood and fetal liver. Total RNA was isolated from each cell population followed by the synthesis of biotinylated cRNA. After fragmentation the biotinylated cRNA was hybridized to affymetrix U133A chips.
2008-10-25 | E-GEOD-6146 | biostudies-arrayexpress
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