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BLOOD COMMENTARIES

REVIEW ARTICLE

Stone et al explore the interconnectiveness of regulation of megakaryopoiesis and regulation of the bone marrow microenvironment in a timely and unique review. In particular, they focus on the now-recognized multiple and divergent pathways from hematopoietic stem cells to mature megakaryocytes and how this is influenced by, and influences, the stem cell niche.

CLINICAL TRIALS AND OBSERVATIONS

San Miguel et al evaluated the impact of dynamic, rather than single-point, assessment of measurable/minimal residual disease (MRD) by next-generation sequencing at a sensitivity of 10−5 during remission on outcome in over 1400 patients in 2 randomized trials of first-line myeloma therapy. MRD negativity sustained over 12 months is associated with superior progression-free survival over either MRD positivity or nonsustained MRD negativity, regardless of frontline treatment regimen.

HEMATOPOIESIS AND STEM CELLS

Increased cellular pH is recognized as a metabolic adaptation by malignant cells. Man and colleagues report that cellular proton balance regulates the proliferation of hematopoietic progenitors and that this is enhanced in acute myeloid leukemia (AML) cells through overexpression of the monocarboxylate transporter MCT4. Inhibition of proton export eradicates leukemia-initiating cells in vivo but does not affect normal hemopoiesis, suggesting a future therapeutic approach for AML.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Funk et al report a potential solution to the problem of exhausted T cells in patients with chronic lymphocytic leukemia (CLL) limiting the efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy. Adding the PI3Kδ/γ inhibitor duvelisib to CAR T-cell cultures from these patients enriches T-stem cell memory and CD8+ CAR T-cell generation and increases in vivo cellular expansion and anti-CLL activity in model systems. This approach is amenable to clinical testing.

LYMPHOID NEOPLASIA

MYELOID NEOPLASIA

THROMBOSIS AND HEMOSTASIS

von Willebrand factor (VWF) platelet-binding activity is proteolytically regulated by ADAMTS13, with congenital or acquired deficiency in ADAMTS13 causing thrombotic thrombocytopenic purpura (TTP) due to an increase in thrombogenic VWF multimer lengths. de Maat and colleagues describe a novel thrombolytic agent that fuses the protease domain of urokinase and a VWF-binding nanobody, thereby targeting plasminogen activation to the VWF surface and degrading fibrin-poor microthrombi. They report amelioration of disease without perturbation of hemostasis in a murine model of TTP.

TRANSPLANTATION

McCurdy et al provide a comprehensive analysis of immune reconstitution after haploidentical and sibling donor allografts using posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. Speed of conventional CD4+ T cell recovery and activation and metabolic signatures are risk markers for acute GVHD. Early natural killer (NK) cell recovery is associated with less relapse, while loss of NK and CD8+ T-cell inflammatory signaling predominates in relapsing patients. These data may inform future interventions following PTCy to improve outcomes.

LETTERS TO BLOOD

Chin and colleagues used detailed mutational analysis of aged mice and transplantation to evaluate the mouse as a model of clonal hematopoiesis (CH). Their data suggest that while murine hematopoietic stem cells acquire mutations in CH-associated genes when aged and CH clones can expand after transplantation (as in humans), these are rare events. Nevertheless, genetically manipulated murine models mimicking human CH are feasible and may prove useful in the future.

BLOOD WORK

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