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BLOOD COMMENTARY

PLENARY PAPER

Life-long persistence of hematopoietic stem cells (HSCs) depends upon maintaining their quiescence. In a Plenary Paper, Liu and colleagues demonstrate that HSC quiescence depends on protein quality control through the unfolded protein response. Endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins maintains HSC quiescence; loss of ERAD causes increased mechanistic target of rapamycin (mTOR) activity, HSC proliferation, and stem cell depletion.

HOW I TREAT

Eichenauer and Engert present their approach to the treatment of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), a rare variant with an overall excellent prognosis. Using 2 illustrative cases, the authors discuss treatment options and choices for low-grade, high-risk, and advanced-stage NLPHL.

CLINICAL TRIALS AND OBSERVATIONS

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare disorder attributable to gain-of-function mutations in the CXCR4 gene. Dale and colleagues report that mavorixafor, an oral CXCR4 receptor antagonist, improves neutrophil and lymphocyte counts, decreases infections, and reduces warts in patients with WHIM syndrome. Although similar responses have been seen with plerixafor, a parenteral CXCR4 inhibitor administered twice daily, mavorixafor is the first oral inhibitor for the treatment of WHIM syndrome and should transform therapy.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Natural killer (NK) cells are important for protection against malignancy. The authors demonstrate that exposure to increased fatty acids in the tumor microenvironment suppresses NK cell function in the setting of lymphoma.

LYMPHOID NEOPLASIA

Activating mutations in VAV1 are seen in mature T-cell neoplasms (TCNs), and Fukumoto et al illuminate their oncogenic role in tumorigenesis in transgenic mice. Transgenic expression of mutant VAV1 on a p53-null background promotes accelerated death from TCNs associated with myc pathway activation.

Chari et al present a large cooperative retrospective study of 650 patients with multiple myeloma with COVID-19 infection. Mortality in hospitalized patients was 33%. Older age, high-risk disease, active or progressive disease, and comorbidities were risk factors for death.

MYELOID NEOPLASIA

Kapp-Schwoerer and colleagues report that minimal residual disease (MRD) negativity following therapy of NPM1-mutated acute myeloid leukemia (AML) is associated with significantly lower relapse rate following chemotherapy. They show that addition of gemtuzumab ozogamicin to intensive chemotherapy results in an increased rate of MRD negativity and a reduction in relapse.

PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Miller et al examined clonal hematopoiesis (CH) in an annotated cohort of adult patients with hemophagocytic lymphohistiocytosis (HLH), reporting that CH is more prevalent in HLH patients than in controls. Furthermore, in a mouse model of adult HLH, Tet2 mutation leads to an exaggerated inflammatory response and more striking HLH findings.

PLATELETS AND THROMBOPOIESIS

Treatment of immune thrombocytopenia (ITP) in pregnancy is usually restricted to steroids and IV immunoglobulin because thrombopoietin receptor agonists (Tpo-RAs) cross the placenta and are not recommended. In a preliminary study of 15 women with severe refractory ITP, the authors report responses to Tpo-RAs in 77% of patients with no serious adverse events and only 1 case of neonatal thrombocytosis.

THROMBOSIS AND HEMOSTASIS

γ′ fibrinogen is an isoform that has anticoagulant properties. The authors performed a Mendelian randomization to elucidate the role of genetically determined levels of γ′ fibrinogen in venous thromboembolism (VTE) and stroke. They demonstrate that higher γ′ fibrinogen levels are protective against VTE, cardioembolic events, and large artery stroke.

TRANSPLANTATION

Myllymäki and colleagues studied the relationship between pretransplant telomere length and survival following hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). Inherited or acquired shortened telomere length in patients with MDS is associated with increased nonrelapse mortality, especially with patients with intensive myeloablative regimens. This suggests that patients with short telomeres pre-HSCT should be considered for less toxic preparative regimens.

LETTER TO BLOOD

BLOOD WORK

ERRATUM

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