Aspects of blast cell proliferation in acute myeloblastic leukaemia

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Kozlowski, R.E., 1991. Aspects of blast cell proliferation in acute myeloblastic leukaemia. PhD, Nottingham Trent University.

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Abstract

The transferrin receptor expression (TfR) of acute myeloblastic leukaemia (AML) blast cells was investigated. Whilst a high percentage (?58%) of AML blast cells were found to express TfRs the degree of TfR expression within each patient's blast cell population was heterogeneous. Suspension culture of the AML blast cells also revealed that their proliferation, as assessed by DNA synthesis, was proportional to their TfR expression.

A fluorescent activated cell sorter allowed AML blast cell populations to be separated into two fractions on the basis of their TfR expression. The fractions with the highest TfR expression were found to contain the majority of blast colony forming cells (AML- CFU). These results indicate AML-CFU are highly proliferative and express high levels of TfR which supports the concept that AML-CFU function as leukaemic stem cells.

AML blast cell proliferation was significantly increased (p≤0.05) at low cell concentrations (≤62.5x103/ml) in round bottomed wells when compared to flat bottomed wells. The enhanced proliferation in round bottomed wells was abrogated when cell to cell contact was inhibited by the addition of latex beads. Following short term suspension cultures of AML blast cells at a low cell concentration(31.25x103/ml) a significantly (p≤0.05) greater number of AML-CFU were recovered from round bottomed wells than from flat bottomed wells. These results demonstrate AML blast cell proliferation is enhanced in crowded cultures and that this phenomenon requires direct cell to cell contact.

As some AML blast cells displayed autonomous proliferation an Autostimulatory Index (ASI) was calculated (no. of colonies without stimulation + no. of colonies with stimulation) and then used to classify patients into four groups. Group 1 non-growers; Group 2 require stimulation (ASI<0.1); Group 3 partially autonomous (ASI 0.1-0.8); Group 4 totally autonomous (ASI>0.8).

Group 3 and Group 4 patients blast cells produce GM-CSF which may regulate their proliferation via autocrine loops. In Group 3 patients blast cells this autocrine loop is inhibited by a specific anti-GM-CSF antibody. In contrast this anti-GM-CSF has no effect on Group 4 patients blast cell proliferation which suggests GM-CSF may act via an intracellular mechanism. These results indicate that GM-CSF production by some AML blast cells can act via autocrine loops. These loops are responsible for the autonomous proliferation of AML blast cells but through heterogeneous mechanisms.

Item Type:

Thesis

Creators:

Kozlowski, R.E.

Date:

1991

ISBN:

9781369324259

Identifiers: