Prolonged response after stopping TPO-RA in ITP, TP53 mutations and myelofibrosis outcomes, clinical picture of ERCC6L2 disease, where variants predispose to marrow failure and malignancy
In this week’s episode we’ll discuss the findings from a prospective trial assessing response after discontinuation of TPO-receptor agonist therapy in primary ITP, learn more about the impact of TP53 on the outcomes of patients with myelofibrosis following hematopoietic stem cell transplant, and review the comprehensive clinical picture of the ERCC-6L2 disease, where germline variants predispose to marrow failure and myeloid malignancies.
CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma
Yao et al explored the mechanism by which CDK7 inhibition mediates multiple myeloma (MM) cell death. They demonstrate that CDK7 expression is correlated with E2F and MYC transcriptional pathways in cells of patients with MM. CDK7 inhibition blocked E2F activity by interrupting the CDK/Rb axis and decreased MYC-regulated metabolic pathways. In primary cells and myeloma mouse models, a small-molecule CDK7 inhibitor killed myeloma cells in vitro and in vivo, suggesting that it is a promising target for clinical treatment of MM.
The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia
Hakkarainen and colleagues describe the natural history of ERCC6L2 disease, a rare homozygous disorder that predisposes to bone marrow failure (BMF) and myeloid malignancies associated with concomitant somatic TP53-mutated clones. They present a retrospective study of 52 patients from 35 families, demonstrating that patients with myelodysplasia have mild cytopenias that belie severe hypoplasia and that progression from BMF to myeloid malignancy is associated with increasing TP53 mutant variant allele fraction and very poor prognosis.
Duodenal macrophages control dietary iron absorption via local degradation of transferrin
Sukhbaatar and colleagues investigated the role of mTORC1 signaling in iron metabolism. They report a novel pathway regulating iron metabolism, demonstrating that mTORC1 regulates macrophages in the lamina propria to induce local degradation of transferrin, limiting iron transfer from intestinal epithelial cells by decreasing availability of transferrin.
Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation
Roullet et al describe a novel approach to the treatment of von Willebrand disease (VWD) using synthetic platelet nanoparticles to bridge von Willebrand factor, collagen, and activated platelets. This preclinical study showed improvement of clotting with microfluidic assays and reduced bleeding in a murine model of VWD.
Always stressed but never exhausted: how stem cells in myeloid neoplasms avoid extinction in inflammatory conditions
While acute and chronic inflammation can cause loss of normal hematopoietic stem cells and lead to hematopoietic failure, they have an opposite impact on myeloproliferative neoplasm stem cells (MPN SCs), driving progression to myeloid malignancy. Zhao and Deininger review the current understanding of the mechanisms by which MPN SCs preserve dormancy to avoid stem cell exhaustion, which may provide insight for noncytoreductive control of MPN cell proliferation.
