Blood Podcast: Season 2, Episode 15
In this week’s episode, we will review a manuscript that describes a novel inherited bone marrow failure syndrome associated with defective clearance of formaldehyde by hematopoietic stem cells, learn about the first large scale analysis of the association between cancer-specific mutations in cancer cells and the incidence of cancer-specific thrombosis, and explore results from a large screening study examining the incidence and progression of monoclonal B cell lymphocytosis in families with an inherited predisposition to chronic lymphocytic leukemia.
Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia–like IBMFS ADH5/ALDH2 deficiency
Mu et al used patient-derived induced pluripotent stem cells (iPSCs) to elucidate the pathophysiology of ADH5/ALDH2 deficiency, a recently described syndrome associated with Fanconi anemia–like bone marrow failure. They demonstrate that ADH5/ALDH2 is critical for protecting progenitors from formaldehyde generated by progenitor cell expansion. Failure of this pathway leads to DNA damage and increased sister chromatid exchange similar to the phenotype of DNA repair pathway mutations in Fanconi anemia.
RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is caused by heterogeneous abnormalities that impair cytotoxic lymphocyte killing of infected and malignant cells, leading to a hyperinflammatory syndrome. Kalinichenko and colleagues describe RhoG deficiency as a novel cause of HLH. The authors demonstrate that RhoG interacts with Munc13-4 (the absence of which also causes HLH) and anchors it to the plasma membrane to facilitate cytotoxic granule release.
Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis
More than 80% of patients with systemic mastocytosis (SM) carry the KIT D816V mutation. Nevertheless, its clinical presentation is heterogeneous, with a wide range of prognoses likely related to secondary accompanying mutations. By creating a panel of patient-specific induced pluripotent stem cells (iPSCs), Toledo and colleagues have provided a powerful tool to investigate patient-specific SM phenotypes and to test for targeted therapies, identifying nintedanib, an angiokinase inhibitor that targets VEGFR, PDGFR, and FGFR, as a novel KIT D816V inhibitor.
Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors
The factors leading to cancer-associated thrombosis (CAT) are still not fully understood. Dunbar and colleagues analyzed the association of tumor-associated somatic mutations and clonal hematopoiesis with thrombotic risk, using more than 14 000 tumor samples. They demonstrate that while clonal hematopoiesis does not increase thrombosis risk, certain tumor-specific mutations increase the risk of CAT independently of tumor type.
Anti-inflammatory activity of CD44 antibodies in murine immune thrombocytopenia is mediated by Fcγ receptor inhibition
Anti-CD44 antibodies have been demonstrated to have anti-inflammatory activity and ameliorate immune thrombocytopenia in murine models. Norris et al have elucidated the mechanism for this effect, demonstrating that the Fc portion of anti-CD44 antibodies inhibits macrophage phagocytosis by blocking Fc receptor–binding sites and thereby blocking phagocytosis of opsonized platelets.
