Dingli, David

Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI − clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI − cells because of a second mutation or a conditional growth advantage of GPI − cells in the presence of an immune attack on normal (GPI + ) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.

Haemopoiesis is a fundamental physiologic process found in many animals. Among mammals, the diversity in size and function required suitable adaptations of this process. In this work, we use allometric principles to determine whether this required a change in the basic architecture of haemopoiesis. We show that it is possible to express both the number and rate with which haemopoietic stem cells replicate as well as total marrow output across all mammals as a function of adult mass. This unified view, which is compatible with the existing data, suggests that there was no need for major adaptations in the architecture of haemopoiesis across mammals.

Treatments for myeloma have expanded in the last decade, but it is not clear if the introduction of novel therapies and the increased use of high-dose therapy have translated into better outcome for patients with myeloma. We examined the outcome of 2 groups of patients seen at a single institution, one from time of diagnosis and the other from the time of relapse, to examine the survival trends over time. Among 387 patients relapsing after stem-cell transplantation, a clear improvement in overall survival from the time of relapse was seen, with those relapsing after 2000 having a median overall survival of 23.9 versus 11.8 months (P < .001) for those who relapsed prior to this date. This improvement was independent of other prognostic factors. Patients treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 vs 14.8 months; P < .001). In a larger group of 2981 patients with newly diagnosed myeloma, those diagnosed in the last decade had a 50% improvement in overall survival (44.8 vs 29.9 months; P < .001). In this study, we demonstrate improved outcome of patients with myeloma in recent years, both in the relapsed setting as well as at diagnosis.

Purpose High-dose therapy with autologous stem-cell transplantation (HDT-ASCT) is now almost standard therapy for many patients with multiple myeloma, partly because of higher complete response (CR) rates. Some studies suggest that tandem transplantation gives superior results. The aim of this study was to determine whether the depth of the response to HDT-ASCT leads to an improvement in time to progression (TTP) and overall survival (OS). We hypothesized that patients with CR before HDT-ASCT (BCR) will have their disease burden reduced further and experience a longer TTP and perhaps OS. Patients and Methods All patients who achieved BCR or CR after HDT-ASCT (ACR) were identified. The characteristics and long-term outcome of these patients were evaluated. Results We identified 14 patients with BCR and 103 patients with ACR who were treated in similar fashion. The patients have been followed for more than 6 years, and the median for OS has not been reached (60-month survival, 55% for BCR and 63% for ACR; P = .83). The median TTP was 43 months for BCR and 34 months for ACR (P = .39). Conclusion The depth of the response in myeloma does not necessarily lead to an improvement in TTP and OS. Tumor dynamics considerations show that the yield from sequential cycles of chemotherapy decreases. Patients who achieve CR with the first transplant can be safely observed without jeopardizing OS.

Abstract The pool of hematopoietic stem cells that actively contributes to hematopoiesis is small, and the cells replicate slowly. Patients with paroxysmal nocturnal hemoglobinuria invariably have a mutation in the PIG-A gene, and many have more than one clone of PIG-A mutated cells. Typically there is a dominant clone and a smaller second clone. By using a combination of stochastic dynamics and models of hematopoiesis, we show that it is very unlikely that more than one PIG-A mutated clone arises at the level of the hematopoietic stem cells. More likely, the smaller clone develops in the progenitor cell pool that would be expected to contribute to hematopoiesis for a shorter period of time. We provide estimates for the duration of these contributions and testable hypotheses that can shed important insights on this acquired hematopoietic stem cell disorder. Disclosure of potential conflicts of interest is found at the end of this article.

AbstractHematopoietic stem cells (HSCs) can both self renew and differentiate into precursors of all types of blood cells. HSCs are divided into an active pool and a quiescent reserve. Cells selected for the active pool contribute to hematopoiesis for many years. Mutations in HSCs can lead to neoplasms such as chronic myeloid leukemia, although the risk of neoplastic HSC disorders varies across mammals. We use allometric scaling relations combined with mutation-selection evolutionary dynamics to determine which mammalian species is most resistant to HSC disorders. We find that the advantage of large mammals at escaping the selective pressure of cancer cells is insufficient to overcome the increased risk of acquiring mutations. Hence, mutation dominates, which favors smaller stem-cell pools and, consequently, smaller mammals, since these minimize the development of mutations in the active stem-cell pool. Consequently, the smaller the active stem-cell pools, the better.

Recently, the size of the active stem cell pool has been predicted to scale allometrically with the adult mass of mammalian species with a 3/4 power exponent, similar to what has been found to occur for the resting metabolic rate across species. Here we investigate the allometric scaling of human haemopoietic stem cells (HSCs) during ontogenic growth and predict a linear scaling with body mass. We also investigate the allometric scaling of resting metabolic rate during growth in humans and find a linear scaling with mass similar to that of the haemopoietic stem cell pool. Our findings suggest a common underlying organizational principle determining the linear scaling of both the stem cell pool and resting metabolic rate with mass during ontogenic growth within the human species, combined with a 3/4 scaling with adult mass across mammalian species. It is possible that such common principles remain valid for haemopoiesis in other mammalian species.

Abstract An abnormal serum immunoglobulin free light chain (FLC) ratio at diagnosis may identify risk of progression to myeloma in patients with solitary bone plasmacytoma (SBP). In the cohort of 116 patients, 43 have progressed to myeloma, with a median time to progression of 1.8 years. The FLC ratio was determined in all 116 patients on serum collected at time of diagnosis and was abnormal in 54 patients (47%). An abnormal FLC ratio was associated with a higher risk of progression to myeloma (P = .039). The risk of progression at 5 years was 44% in patients with an abnormal serum FLC ratio at diagnosis compared with 26% in those with a normal FLC ratio. One to 2 years following diagnosis, a persistent serum M protein level of 5 g/L (0.5 g/dL) or higher was an additional risk factor for progression. A risk stratification model was constructed using the 2 variables of FLC ratio and M protein level: patients with a normal FLC ratio at baseline and M protein level less than 5 g/L (0.5 g/dL) at 1 to 2 years following diagnosis (low risk, n = 31); with either risk factor abnormal (intermediate risk, n = 26); and with both an abnormal FLC ratio and M protein level of 5 g/L (0.5 g/dL) or higher (high risk, n = 18). The corresponding progression rates at 5 years were significantly different in the low, intermediate, and high groups: 13%, 26%, and 62%, respectively (P < .001).