Recurrent mutations in calreticulin are present in ∼20% of patients with myeloproliferative neoplasms (MPNs). Since its discovery in 2013, we now have a more precise understanding of how mutant CALR, ...an endoplasmic reticulum chaperone protein, activates the JAK/STAT signaling pathway via a pathogenic binding interaction with the thrombopoietin receptor MPL to induce MPNs. In this Spotlight article, we review the current understanding of the biology underpinning mutant CALR-driven MPNs, discuss clinical implications, and highlight future therapeutic approaches.
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Some cancers originate from a single mutation event in a single cell. Blood cancers known as myeloproliferative neoplasms (MPNs) are thought to originate when a driver mutation is acquired by a ...hematopoietic stem cell (HSC). However, when the mutation first occurs in individuals and how it affects the behavior of HSCs in their native context is not known. Here we quantified the effect of the JAK2-V617F mutation on the self-renewal and differentiation dynamics of HSCs in treatment-naive individuals with MPNs and reconstructed lineage histories of individual HSCs using somatic mutation patterns. We found that JAK2-V617F mutations occurred in a single HSC several decades before MPN diagnosis—at age 9 ± 2 years in a 34-year-old individual and at age 19 ± 3 years in a 63-year-old individual—and found that mutant HSCs have a selective advantage in both individuals. These results highlight the potential of harnessing somatic mutations to reconstruct cancer lineages.
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•Single-cell transcriptome and whole-genome sequencing of HSPCs from individuals with MPNs•The JAK2-V617F mutation occurs in a single HSC decades before diagnosis•JAK2-V617F HSCs have increased fitness in native human hematopoiesis•JAK2 mutant fraction varies in myeloid progenitor compartments in the same individuals
Van Egeren et al. investigated the effect of the JAK2-V617F mutation in individuals with myeloproliferative neoplasms (MPNs) using single-cell profiling and found that the mutation occurs decades before MPN diagnosis and increases the fitness of HSCs. JAK2-V617F induces a megakaryocyte-erythroid differentiation bias. The JAK2-mutant fraction varies in myeloid compartments in the same individuals.
Background and purposeCombining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific ...and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic proceduresWe used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findingsRegorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusionsJudicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have ...clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera. Additional JAK2 inhibitors are currently in advanced phased clinical trials.
The introduction of next-generation sequencing has broadened the genetic landscape of myeloproliferative neoplasms (MPNs) beyond JAK2, MPL, and CALR. However, the biological role and clinical impact ...of most other mutations are not well defined. We interrogated 101 genes in 143 BCR-ABL1-negative MPNs in chronic phase from 2 large institutions. We detected SF3B1 mutations in 15 cases (10%) and set to investigate the clinical, morphologic, and molecular features of SF3B1 mutated (SF3B1+) MPNs in comparison to SF3B1 wild-type (SF3B1−) cases and to identify distinctive features with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts (RS) and thrombocytosis, which can show partial clinical and morphological overlap with MPNs. SF3B1+ cases were enriched in primary myelofibrosis in both prefibrotic and fibrotic stage, but mutations of SF3B1 seem to occur only as a late event in the fibrotic phase of essential thrombocythemia and polycythemia vera. SF3B1+ MPNs showed borderline lower hemoglobin but no other clinical or molecular differences compared to SF3B1− MPNs. Of note, RS were present only in a subset of SF3B1+ cases (4/10) without any other feature of erythroid or granulocytic dysplasia. Our results suggest that mutations in SF3B1 are not a rare event in MPNs, especially in primary myelofibrosis and during late fibrotic stages of essential thrombocythemia and polycythemia vera, but are not associated with myelodysplastic progression. Careful examination of bone marrow and peripheral blood for morphologic dysplasia is crucial to reach the correct diagnosis and avoid a misdiagnosis of myelodysplastic/myeloproliferative neoplasms with RS and thrombocytosis, a pitfall with potential prognostic and therapeutic implications.
•SF3B1 mutations are seen in 10% of BCR-ABL1–negative myeloproliferative neoplasms.•SF3B1 mutations are seen predominantly in PMF in both prefibrotic and fibrotic stages.•In ET and PV, SF3B1 mutations seem to be a later event.•Ring sideroblasts are present only in a subset of SF3B1-mutated cases.•Presence of SF3B1 mutation is not associated with dysplastic progression.
The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood.
We performed a prospective cohort study of adults with solid-organ or hematologic cancers ...to evaluate anti-SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison.
Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log
geometric mean concentration GMC 2.9, log
geometric mean neutralization titer GMT 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4;
< .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses (
< .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type (
< .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses (
= .002 for concentration,
= .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose).
Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the ...seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis. We summarize recent studies delineating the genetic basis of PV, including their implications for evolution to myelofibrosis and secondary acute myeloid leukemia. We assess the quality of evidence to support the use of currently available therapies, including aspirin, phlebotomy, hydroxyurea, and interferon. We analyze recent studies evaluating the safety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of other available therapies for PV. This review provides a framework for practicing hematologists and oncologists to make rational treatment decisions for patients with PV.
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