Hematopoietic differentiation is characterized by a transient peak of entropy at a single-cell level.

BACKGROUND: Mature blood cells arise from hematopoietic stem cells in the bone marrow by a process of differentiation along one of several different lineage trajectories. This is often represented as a series of discrete steps of increasing progenitor cell commitment to a given lineage, but as for differentiation in general, whether the process is instructive or stochastic remains controversial. Here, we examine this question by analyzing single-cell transcriptomic data from human bone marrow cells, assessing cell-to-cell variability along the trajectories of hematopoietic differentiation into four different types of mature blood cells. The instructive model predicts that cells will be following the same sequence of instructions and that there will be minimal variability of gene expression between them throughout the process, while the stochastic model predicts a role for cell-to-cell variability when lineage commitments are being made. RESULTS: Applying Shannon entropy to measure cell-to-cell variability among human hematopoietic bone marrow cells at the same stage of differentiation, we observed a transient peak of gene expression variability occurring at characteristic points in all hematopoietic differentiation pathways. Strikingly, the genes whose cell-to-cell variation of expression fluctuated the most over the course of a given differentiation trajectory are pathway-specific genes, whereas genes which showed the greatest variation of mean expression are common to all pathways. Finally, we showed that the level of cell-to-cell variation is increased in the most immature compartment of hematopoiesis in myelodysplastic syndromes. CONCLUSIONS: These data suggest that human hematopoietic differentiation could be better conceptualized as a dynamical stochastic process with a transient stage of cellular indetermination, and strongly support the stochastic view of differentiation. They also highlight the need to consider the role of stochastic gene expression in complex physiological processes and pathologies such as cancers, paving the way for possible noise-based therapies through epigenetic regulation.

Improved survival in HIV-related Hodgkin's lymphoma since the introduction of highly active antiretroviral therapy.

OBJECTIVE: To evaluate the evolving characteristics of HIV-related Hodgkin's lymphoma (HL) and survival of affected patients since the introduction of highly active antiretroviral therapy (HAART). DESIGN AND METHODS: A retrospective single-institution study was performed over a 15-year follow-up period. For statistical analysis, patients were categorized into a pre-HAART period (1987-1996, n = 61) and a post-HAART period (1997-2001, n = 47). RESULTS: HL characteristics were similar in both groups. The chemotherapy regimens used did not differ significantly, although the MOPP/ABV regimen (mechlorethamine, vincristine, procarbazine substituted by cyclophosphamide since 2000, and prednisone /adriamycin, bleomycin, vinblastin) has progressively replaced the ABVD regimen (adriamycin, bleomycin, vinblastin, dacarbazine). A slight increase in the complete response rate was noted in the post-HAART population (74.5%) versus the pre-HAART population (64.5%), and the probability to relapse was not different between the two groups. Patients diagnosed since 1997 had a higher probability for prolonged survival with a median survival time not reached versus 19 months in the pre-HAART period. The estimate 2-year survival probability was 45% [95% confidence interval (CI), 32.3-57.8% in the pre-HAART period, and 62% (95% CI, 46.7-77.1%) in the post-HAART period ( P= 0.03). This decreased mortality was associated with a decrease in AIDS-associated deaths. In the post-HAART period, 12 patients were naive to any antiretroviral therapy and 31 were already on HAART at the time of HL diagnosis. Twenty of them had a plasma HIV-RNA below 500 copies/ml. The response rate and the overall survival were not statistically different in these patients. CONCLUSIONS: HL still occurs in patients with HAART-induced HIV suppression. However, overall survival has significantly improved since the introduction of HAART.

Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival.

The incidence of systemic non-Hodgkin lymphoma (NHL) has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART), suggesting that current antiretroviral strategies do not eliminate the lymphoma risk. This study evaluates the evolving characteristics of HIV and NHL between the pre-HAART and the post-HAART periods in 246 HIV-infected NHL patients from a single institution. Major HIV-related characteristics were similar in the two periods. Most patients in the post-HAART period presented with unknown (23%), untreated (16%), or uncontrolled (37%) HIV infection. Despite an increased frequency of advanced stage IV disease in the post-HAART period (68% vs. 53%, p =.03), the overall survival has improved, with a 2-year survival probability of 61.6% versus 35.9%, (p <.001). This was associated with an increased complete remission rate (69% vs. 55%, p =.04) and the generalization of more intensive chemotherapy regimens. Most patients (76%) who developed NHL in the post-HAART period had uncontrolled HIV replication. However, 27 patients (24%) developed NHL despite an effective viral suppression at NHL diagnosis. Patients who were naive to any antiretroviral therapy at NHL diagnosis had an overall survival probability very similar to that of patients with controlled HIV replication. Improvement in the overall survival rate in the post-HAART period was associated with more intensive chemotherapy regimens, increased complete remission rate, and a likely benefit of continuation or introduction of HAART.