CD26/DPP-4 in Chronic Myeloid Leukemia

Abstract

CD26 expression is altered in many solid tumors and hematological malignancies. Recently, it has been demonstrated that it is a specific marker expressed on LSCs of CML, both in BM and PB samples, and absent on CD34+/CD38− stem cells in normal subjects or on LSCs of other myeloid neoplasms. CD26+ LSCs have been detected by flow-cytometry assays in all PB samples of Chronic-Phase CML patients evaluated at diagnosis. Additionally, it has been demonstrated that most CML patients undergoing Tyrosine Kinase Inhibitors (TKIs) treatment still harbored circulating measurable residual CD26+ LSCs, even when displaying a consistent deep molecular response without any significant association among the amounts of BCR-ABL transcript and CD26+ LSCs. Preliminary data of our Italian prospective multicenter study showed that CML patients with a poorer response presented with a higher number of CD26+ LSCs at diagnosis. These data confirmed that CD26 is a specific marker of CML and suggest that it could be considered for the monitoring of therapeutic responses.

CD26 and Cancer

“…CD26 expression has been associated with the early aggressiveness of T and B cell lymphomas and leukaemia [ 32 ]. A partial recent review of CD26 in haematological malignancies [ 13 ] is completed here with the reviews performed by the group of Lettau and Sicuranza et al [ 33 , 34 ]. CD26/DPP4 expressed on T cell lymphoblastic lymphoma (T-LBL), T cell acute lymphoblastic leukaemia (T-ALL), T-ALCL (anaplastic large cell lymphoma), T-large granular lymphocyte lymphoproliferative disorder (T-LGL LPD), B-chronic lymphocytic leukaemia (B-CLL), or multiple myelomas (MMs, when associated with osteoclasts) has been associated with poor survival and associations with cell adhesion.…”

“…However, in cutaneous T cell lymphoma (CTCL,) including the most frequent CTCL mycosis fungoides (MF) and Sézary syndrome (SS), the expression is lost with disease progression (associated with lower serum CD26/DPP4 levels). In this case, this loss induces the migration of SS cells by a reinforced chemoattraction [ 34 ].…”

“…Some of the chemokines cited above responsible for metastatic cell migration should be removed at that moment. Additional pathways reviewed in the Special Issue show where CD26 is implicated in cancer as the ADA partner in the metabolism of nucleotides, very active in tumour tissues [ 33 , 34 ].…”

“…However, DPP4 participates with other cell surface proteases in malignant transformation and cancer progression by facilitating invasion [ 35 , 36 , 37 ], as was first suggested by Werb [ 38 ]. In this sense, the knowledge acquired in recent years about cancer stem cells (CSCs) is remarkable, as is the fact that subsets of CSCs expressing CD26 have been implicated in metastases of many cancers [ 13 , 31 , 39 ], including haematological (leukemic stem cells or LSCs, reviewed in [ 34 ]). In contrast to other tested antigens co-expressed on chronic myeloid leukaemia (CML) LSCs, acute myeloid leukaemia (AML) LSCs, and normal HSCs, CD26 is the only marker which is not present on CD34+/CD38− normal stem cells, and the expression levels of these cells are associated with prognosis of the disease [ 34 ].…”

“…Notably, DPP4i do not block CD26-dependent cell aggregation [ 31 ], which is coherent with the fact that fibronectin and/or ecto-ADA bind to epitopes of CD26 that do not involve its catalytic site. In addition, CD26 and polycomb BMI1, a stem cell factor, are co-expressed in LSCs [ 34 ], with BMI1 inhibition showing promising results in the treatment of chemo-resistant cancers [ 41 ].…”