Issue Archive

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.

The European LeukemiaNet guidelines, the World Health Organization classification, and the International Consensus Classification have all been recently updated to provide new guidance on classification reflecting molecular abnormalities, risk stratification, prognosis, response assessment, and measurable residual disease monitoring for patients with acute myeloid leukemia (AML). In a timely How I Treat article, El Chaer et al use 4 illustrative cases to discuss how changes in these classification systems and guidelines influence clinical decision making.

Jaeger et al elucidated the role of neutrophils in peripheral T-cell lymphomas with a strong inflammatory phenotype. The authors focused on follicular T-cell lymphoma (T-follicular helper type). They show that these tumors induce inflammation and neutrophil expansion accompanied by marked cytokine release. Depletion of neutrophils, removal of interleukin-6, and inhibition of JAK-STAT signaling with ruxolitinib all reduced inflammation and tumor progression.

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.

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.

Guillet et al present results of thrombopoietin receptor agonist (TPO-RA) discontinuation in a selected population of patients with persistent or chronic immune thrombocytopenia (ITP). They report that in patients in stable remission with a platelet count of >100 × 10⁹/L for at least 2 months (48 of 388 patients), 56% maintained a platelet count of >30 × 10⁹/L off therapy. This suggests that a subset of patients on chronic treatment with TPO-RA can be successfully tapered off therapy.

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.

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.

Mutations in TP53 are associated with poor prognosis in many hematologic malignancies. Gagelmann et al confirmed that this is also true for patients with myelofibrosis who undergo hematopoietic stem cell transplantation. In an analysis of 349 patients, 49 had TP53 mutations, and 30 of the 49 had multihit mutations. As with patients with acute leukemia, patients with single-hit mutations have survival rates similar to those with wild-type TP53. However, patients with multihit TP53 mutations have a shorter time to leukemic transformation and a markedly reduced median survival (1.5 years vs 13.5 years with wild-type TP53).