Acute leukaemia: development, remission/relapse pattern, relationship between normal and leukaemic haemopoiesis, and the ‘sleeper-to-feeder’ stem cell hypothesis

Abstract

Attention has been focused on two problems of acute leukaemia: (1) the origin of normal-appearing haemopoietic cells during relapse, and (2) the inverse relationship between leukaemic blast cell proliferation and useful haemopoietic cell production. The available evidence suggests that the normal-appearing cells during relapse may not all be remnants of normal haemopoiesis but may at least in part be derived from leukaemic cells. Although a differentiation defect is a major characteristic of acute leukaemia, it seems as if this defect is not absolute: some cells may succeed in differentiating more or less normally in spite of their descent from a leukaemic stem cell. Acute leukaemia is usually considered to be a primary white cell disorder which indirectly affects the other haemopoietic cell lines. It appears more likely, however, that acute leukaemia, at least the myeloid type, is a disorder of a stem cell common to granulocytopoiesis, erythropoiesis, and probably thrombocytopoiesis. Most descendants from the diseased stem cell fail to differentiate and remain at the blast cell level where they proliferate for some time; however, at a certain point proliferation ceases and the cells ultimately die. Another fraction of the progeny of the leukaemic stem cells may differentiate to some extent and may give rise to functionally useful cells. This is analogous to chronic myeloid leukaemia. The mechanism by which useful haemopoiesis apparently is suppressed in the presence of leukaemic blast cells has remained enigmatic so far. Previously suggested explanations which all assume some kind of cell-cell interaction by which normal haemopoietic cells succumb have neither been proved nor disproved. In this chapter, a new hypothesis is presented. It is assumed that some normal haemopoietic stem cells enter a dormant state at various distances in lineage from the fertilized ovum ('sleepers'). Another fraction of haemopoietic stem cells ('feeders') are actively proliferating and serve to feed the differentiating haemopoietic cell lines and to maintain the 'feeder' pool. When the 'feeder' pool is exhausted, a 'sleeper' cell is activated and sets up a new 'feeder' clone. Otherwise, 'sleepers' are protected against acting as 'feeders' in order to keep 'sleeper' divisions at a minimum and thus preserve their genetic information as intact as possible. It is suggested that the leukaemic event initially takes place in one or a few 'sleepers'. If the leukaemic 'sleeper' never succeeds in setting up a 'feeder' clone, clinical leukaemia will not develop. Clinical leukaemia will result if a leukaemic 'sleeper' establishes a leukaemic 'feeder' pool.(ABSTRACT TRUNCATED AT 400 WORDS)