Preferential sequestration in vitro of BCR/ABL negative hematopoietic progenitor cells among cytokine nonresponsive CML marrow CD34+ cells

Abstract

Summary:cells. These studies also confirm the feasibility of employing negative hematopoietic regulators to augment the sequestration of normal HPC among the cytoIt is believed that long-term cultures of CML marrow cells favor the outgrowth of BCR/ABL negative hematokine nonresponsive fraction of CD34 ؉ cells, an approach that may be clinically feasible for autotranspoietic progenitor cells (HPC) primitive hematopoietic progenitor cells (HPC) within (MIP-1␣/CNR) supported a higher and, in some CML marrow. [7][8][9][10][11] The first documentation of the existence patients, a more extended production of clonogenic of normal primitive HPC in CML marrow was presented HPC, indicating that MIP-1␣ was able to maintain by Coulombel et al 12 who then went on to demonstrate that primitive HPC in a quiescent state. Predominance of although these cells remain dormant in vivo, they can be BCR/ABL negative progenitors in vitro was more eviactivated, and therefore detected and selected, in vitro. [13][14][15] al 10 and by our group 11 to be enriched for BCR/ABL their isolation from the more actively cycling leukemic negative HPC. Biological substances with inhibitory hematopoietic activities such as transforming growth factor-beta1 (TGF-

Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation

“…In the future, it will be important to explore the possibility that, in addition to the direct effects on progenitor growth described here, imatinib mesylate may indirectly affect progenitor growth by correcting abnormalities in responsiveness to microenvironmental influences such as ligands for adhesion 30,[35][36][37] and chemokine receptors. [38][39][40] Our studies suggest that short-term exposure to imatinib mesylate ex vivo may not be sufficient to eliminate malignant progenitors. This indicates that use of imatinib mesylate alone may not adequately deplete malignant stem cells from CML autografts.…”

Primitive human HPCs are better maintained and expanded in vitro at 1 percent oxygen than at 20 percent

“…Every week, one‐half of the liquid culture suspension was removed and replaced with fresh medium and growth factors. The harvested cells were then counted and replated in semisolid cultures to determine the liquid culture content of committed clonogenic progenitors, that is, the maintenance in primary cultures of primitive progenitors endowed with CFU–GM generation potential 15,16 …”

A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts

“…23 The latter is manifested as a 450-fold decline in LTC-IC activity in vitro within 10 days under conditions where normal LTC-IC numbers are maintained or increase. 20,40 Additional studies are in progress to determine whether this treatment maintains sufficient numbers of repopulating cells, and to investigate whether in vivo recovery of transplanted patients would be achieved. It would also be of interest to determine whether the addition of Flt3-ligand to the expansion medium would improve the normal hematopoietic activity of the treated cells since this cytokine has been demonstrated to improve their amplification in other studies.…”