Auto-SCT induces a phenotypic shift from CMP to GMP progenitors, reduces clonogenic potential and enhances in vitro and in vivo cycling activity defined by 18F-FLT PET scanning

Abstract

Autologous SCT (auto-SCT) introduces a reduced tolerance to chemotherapy even in patients with adequate engraftment, suggesting long-term effects of the transplantation procedure on the BM capacity. To study the hematopoietic cell compartment after auto-SCT, CD34 þ BM cells (n ¼ 16) from patients at 6-9 months after auto-SCT were studied with regard to the progenitor subsets, colony frequency and cell cycle status. The BM compartments were studied in vivo using PET tracer 3-fluoro-3-deoxy-Lthymidine ( 18 F-FLT PET). BM CD34 þ cells after auto-SCT were compared with normal CD34 þ cells and showed a phenotypic shift from common myeloid progenitor (CMP mean percentage 3.7 vs 19.4%, P ¼ 0.001) to granulocytemacrophage progenitor (GMP mean percentage 51.8 vs 27.6%, P ¼ 0.01). In addition, a reduced clonogenic potential and higher cycling activity especially of the GMP fraction (41% ± 4 in G2/S phase vs 19% ± 2, P ¼ 0.03) were observed in BM after auto-SCT compared with normal. The enhanced cycling activity was confirmed in vivo by showing a significantly higher uptake of the 18 F-FLT PET tracer by the BM compartment. This study shows that auto-SCT results in defects of the hematopoietic compartment at least 6 months after auto-SCT, characterized by changes in the composition of progenitor subsets and enhanced in vitro and in vivo cycling activity.

F-18 FLT PET: A Noninvasive Diagnostic Tool for Visualization of the Bone Marrow Compartment in Patients With Aplastic Anemia

“…[7][8][9] In myelodysplasia, a homogenous elevated F-18 FLT uptake of the bone marrow compartment was demonstrated, whereas in myelofibrosis, a highly increased uptake of the spleen was seen as result of extramedullary hematopoiesis. 8 Therefore, F-18 FLT PET may be helpful in differentiating between these hematological disorders.…”

“…In many tumor types, good correlations between proliferative activity and F-18 FLT uptake have been demonstrated. 9 F-18 FLT acts as a chain terminator and is only marginally incorporated into DNA and therefore not a direct measure of proliferation. 11,12 In vitro studies indicate that F-18 FLT uptake is closely related to thymidine kinase 1 activity, as well as to expression of nucleoside transporters in the cellular membrane and reflects S-phase fraction rather than DNA synthesis.…”

“…[5][6][7] This is in line with the enhanced bone marrow F-18 FLT uptake in patients with myelodysplasia and myelofibrosis and patients following autologous stem cell transplantation. 8,9 On the basis of these findings, we studied the bone marrow compartment in patients with AA and compared the results with clinical parameters.…”

PET Imaging of Proliferation with Pyrimidines

“…Although this review discusses some studies about detecting bone tumors and metastases, bone marrow uptake is one of the limiting factors in applying 18 F-FLT PET in cancer staging, along with liver uptake. However, 18 F-FLT PET also has been used to measure the health and proliferation of the marrow, especially in patients undergoing bone marrow transplantation (12). 18 F-FLT PET imaging was found useful in evaluating bone marrow in patients with aplastic anemia (13).…”

Loss of quiescence and impaired function of CD34+/CD38low cells one year following autologous stem cell transplantation

“…6,7 These findings are in line with our recent observations demonstrating a shift within the CD34 + progenitor cell compartment post-ASCT towards phenotypically defined granulocyte/macrophage progenitors (GMPs), which coincided with a reduced clonogenic potential and enhanced cell cycle activity. 8 After allogeneic stem cell transplantation, a higher cycling activity of CD34 + CD90…”