Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells

Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.Jacobsen and colleagues elucidate the nonhierarchical relationship between two types of stem cells: Vwf - hematopoietic stem cells that stably replenish all blood cell lineages without a platelet bias, and Vwf + stem cells that replenish almost exclusively platelets, and demonstrate that the two types utilize cellularly and molecularly distinct progenitor trajectories for replenishment of platelets

Identification and surveillance of rare relapse-initiating stem cells during complete remission post-transplantation.

Relapse following complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and therefore improved biomarkers for early prediction of relapse remains a critical goal towards development and assessment of preemptive relapse treatment. Since the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse-prediction post-transplantation. In a retrospective study of relapse patients and continuous-CR patients with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in bone marrow at multiple CR time points post-transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by more than 2 years. In distinction, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD-sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean 8-fold).In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD-screening for their persistence consistently enhances MRD-sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

Abstract Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes