Deficient proliferation and expansionin vitroof two bone marrow cell populations from patients with acute myeloid leukemia in response to hematopoietic cytokines

Abstract

One has previously characterized two different hematopoietic cell populations (obtained by negative-selection) from normal bone marrow. Population I was enriched for CD34+ Lin- cells, whereas Population II was enriched for CD34+ CD38- Lin- cells. Both populations showed elevated proliferation and expansion potentials in serum-free liquid cultures, supplemented with a combination of eight different cytokines, with the latter displaying more immature features than the former. One has also characterized the chronic myeloid leukemia (CML) counterparts of these two populations and demonstrated functional deficiencies in terms of their growth in culture. In keeping with this line of research, the goal of the present study was to obtain the same two populations (Populations I and II) from acute myeloid leukemia (AML) bone marrow and to characterize their biological behavior under the same culture conditions. The results demonstrated that AML-derived Populations I and II were unable to proliferate in culture conditions that allowed significant proliferation of Populations I and II from normal marrow. Population I from AML also showed a deficient expansion capacity; in contrast, Population II cells were able to expand to a similar extent to the one observed for Population II from normal marrow. Both normal and AML populations were highly sensitive to the inhibitory effects of TNF-alpha; interestingly, whereas in normal fractions TNF-alpha showed a more pronounced inhibitory effect on more mature cells (Population I), this cytokine inhibited proliferation and expansion of AML Populations I and II in a similar degree. It is noteworthy that the functional deficiencies observed in AML cells were even more pronounced than those previously reported for cultures of CML cells. The results reported here may be of relevance considering the interest by several groups in developing methods for the in vitro purging of leukemic cells, as part of protocols for autologous transplantation of hematopoietic cells in leukemic patients.

Involvement of Oxidative Stress in the Relapse of Acute Myeloid Leukemia

“…Disturbances to oxidative stress metabolism are commonly associated with tumor cells, and the level of oxidative stress among patients increases with disease severity and the accumulation of chromosomal aberrations (22,23). Leukemias originate from hematopoietic stem cells that lose the capacity to differentiate normally into mature blood cells (24,25). Although most patients achieve complete remission after chemotherapy, most of them suffer a subsequent leukemia relapse, which is associated with poor long term survival.…”

CD99 is a therapeutic target on disease stem cells in myeloid malignancies

“…When the CD99-high and CD99-low populations from both CD34 + and CD34 − AMLs were cultured in vitro in liquid culture supplemented with cytokines, CD99-high cells demonstrated improved viability compared with CD99-low cells (fig. S7), a previously described characteristic of LSC-enriched blasts in AML (24,25).…”

Serum cytokine and adhesion molecule profile differs in newly diagnosed acute myeloid and lymphoblastic leukemia

“…[4][5][6] ). Alterations in this interacting functional network may have direct effect on the malignant cells or have indirect effect on leukemogenesis through altered functions of bone marrow stromal elements [7][8][9] . The knowledge gained from multi-analytical determination of cytokines and adhesion molecules could allow better diagnosis and management of hematological malignancies, since cytokines or their receptors may also represent a target for specific anticancer therapy at the molecular level.…”