Cell Cycling Stress in the Monocyte Line as a Risk Factor for Progression of the Aplastic Anaemia/Paroxysmal Nocturnal Haemoglobinuria Syndrome to Myelodysplastic Syndrome

Abstract

Severe aplastic anaemia (SAA) causes permanent stem cell damage from which patients do not recover after treatment with antilymphocyte globulin (ALG). To produce peripheral blood values compatible with life, the few remaining stem and precursor cells are put under stress. We defined a ‘stress factor’ (SF) for various haematopoietic lines as the ratio of the corresponding peripheral blood (PB) value to the total colony number in short-term bone marrow cultures from 86 patients with different outcomes. Both values are expressed as percentage of normal, hence SF averages 1 in normal steady-state haematopoiesis. SF was elevated in all patients, from 2-to 40-fold, with wide variations in different patient groups and striking differences between haematopoietic lineages. In long-term disease-free survivors after ALG (group 1) the mean total colony count was 19% of normal, with a significantly higher proportion of erythroid burst-forming units compared to normal. They had ineffective erythropoiesis with haemoglobin (Hb) values below, and reticulocyte counts above normal; platelet counts were 67% of normal. In contrast, monocyte counts were in the high normal range, resulting in a high SF (18.7 ± 1.9) for monocytes. In patients who developed paroxysmal nocturnal haemoglobinuria (PNH) after ALG (group 2), ineffective erythropoiesis, reflecting haemolysis, was more pronounced and they had striking relative monocytosis, resulting in a significantly higher SF for monocytes (33.7 ± 5.7) compared with group 1 (p < 0.0001). High monocyte counts most likely reflect the relative resistance of nucleated cells to complement, compared with red cells and platelets. Patients who developed myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) after ALG, with or without PNH (group 3), had the highest SF for monocytes (39 ± 10). They also had neutrophil counts in the upper range, or above normal, resulting in a high SF for neutrophils: 32 ± 19. In patients with persisting or relapsing-remitting pancytopenia without a clinically detectable clonal disorder (group 4), all values were strikingly similar to those of the PNH group. In patients who achieved normal PB values after uncomplicated bone marrow transplantation (group 5), the SF averaged 3, but they also had ineffective erythropoiesis and mild relative monocytosis, a possible sign of occult PNH. We conclude that all patients after treatment of SAA have ineffective erythropoiesis and relative monocytosis, and that these abnormalities probably reflect PNH. We suggest that the resulting high SF for the leukocyte – particularly the monocyte line – predisposes to the development of MDS/AML. We discuss how these results may provide some of the missing pieces in the puzzle of SAA/PNH.

Riddle: What do aplastic anemia, acute promyelocytic leukemia, and chronic myeloid leukemia have in common?

“…Replicative stress to the residual normal hematopoietic progenitor compartment has been proposed as a mechanism of secondary clonal disease in SAA. 28 However, this is unlikely to be a mechanism for MDS after ATRA in APL and imatinib in CML, as it would be expected to produce secondary clonal disease in the setting of nonspecific cytotoxic therapy as well. The coexistence of small abnormal clones, in addition to the dominant disease, could limit the therapeutic effectiveness of all targeted therapies being developed for acquired bone marrow disorders.…”

Protective Effects of Chronic Intermittent Hypobaric Hypoxia Pretreatment against Aplastic Anemia through Improving the Adhesiveness and Stress of Mesenchymal Stem Cells in Rats

“…There is a great number of adhesion ligands on the surface of BMMSCs, which can combine to adhesion receptors on the surface of hematopoietic stem/progenitor cells. So BMMSCs are often described as the soil of HSCs and play a key role in hematopoiesis through stimulating the proliferation and differentiation of hematopoietic stem/progenitor cells [ 36 ] or through the extracellular medium [ 7 ]. Therefore, the abnormality of adhesion ligand expression in BMMSCs will affect the growth of hematopoietic stem/progenitor cells in the bone marrow microenvironment.…”