Elsevier

Neoplasia

Volume 20, Issue 6, June 2018, Pages 632-642
Neoplasia

Phenotyping and Target Expression Profiling of CD34+/CD38 and CD34+/CD38+ Stem- and Progenitor cells in Acute Lymphoblastic Leukemia

https://doi.org/10.1016/j.neo.2018.04.004Get rights and content
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open access

Abstract

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.

Abbreviations

ALL
acute lymphoblastic leukemia
BM
bone marrow
CML
chronic myeloid leukemia
GO
gemtuzumab-ozogamicin
LSC
leukemic stem cell
MNC
mononuclear cell
NSG
NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ
OS
overall survival
PB
peripheral blood
Ph
Philadelphia chromosome
SCT
stem cell transplantation
TKI
tyrosine kinase inhibitor

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