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

摘要

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/ABL1 _(p210), whereas in Ph ~(+) ALL with BCR/ABL1 _(p190), 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/ABL1 _(p210), 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.