JAK2 Mutations Rarely Found in Patients With MPN Living in High Altitude Areas Who Have Unprovoked Thrombotic Events

Posted on November 14, 2024November 14, 2024 by mpn_admin

Ryner Lai

November 12, 2024

JAK2 mutations are rarely found in patients with a myeloproliferative neoplasm (MPN) who have unprovoked thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), or atypical thrombosis — living in high-altitude regions, according to a study published in the International Journal of General Medicine.

Thrombosis often serves as the initial manifestation of a MPN and is a significant contributor to both morbidity and mortality. JAK2 plays a role in influencing the proliferation of hematopoietic cells and the inflammatory signaling cascade; mutation in JAK2 is notably associated with higher rates of cellular proliferation and differentiation, as well as cytokine release. Patients with MPNs and JAK2 mutations typically have a raised risk of thrombosis when compared with their counterparts who do not have JAK2 mutations.

High-altitude living is associated with alterations in coagulation pathways and blood composition. Studies demonstrate that otherwise healthy individuals with high-altitude hypoxia are at an increased risk of developing idiopathic arterial and venous thrombosis. Scientists suspect that the high altitude can interact with background hereditary/acquired thrombophilia to further exacerbate the risk of initial/recurrent thrombosis.

Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms

Posted on February 13, 2024February 13, 2024 by mpn_admin

Taylor B. Collins, Angelo B.A. Laranjeira, Tim Kong, Mary C. Fulbright, Daniel A.C. Fisher, Christopher M. Sturgeon, Luis F.Z. Batista, and Stephen T. Oh

Abstract

Myeloproliferative neoplasms (MPN) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induce a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated MPN disease burden including leukemic engraftment and splenomegaly in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only to primary MPN samples harboring ASXL1 mutations. Lastly, treatment of CD34+ hematopoietic/stem progenitor cells with PRMT6 inhibitor, EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.

A Rare Coexistence of Smoldering Multiple Myeloma and JAK2-Positive Myeloproliferative Neoplasm: A Case of Dual Synchronous Hematological Malignancy

Posted on January 29, 2024January 29, 2024 by mpn_admin

January 20, 2024

Abstract

This article explores the rare case of an 82-year-old man diagnosed concurrently with essential thrombocythemia and smoldering multiple myeloma (SMM). The limited existing literature on individuals harboring both myeloproliferative neoplasm (MPN) and monoclonal gammopathy (MG) is of significant interest due to the distinct origins of these malignancies. The etiology of MG in MPN patients remains elusive, leading to speculation about a potential relationship or interplay between the two conditions. This unique case prompts a deeper exploration of the mechanisms underlying the coexistence of JAK2-positive MPN and SMM. It underscores the importance of tailored therapeutic strategies that carefully consider the inherent risks and potential adverse outcomes associated with these specific malignancies, thereby warranting further clinical research.

Introduction

While existing literature acknowledges the coexistence of dual malignancies within the same patient [1], there is relatively limited documentation regarding the simultaneous occurrence of dual hematological malignancies (DHMs) [2,3], encompassing both myeloid and lymphoid hemopathies. A noteworthy aspect is the distinctive origin of these two malignancies from separate lineages within the hematopoietic ancestral tree [4]. DHMs can be classified as synchronous, manifesting within six months of the initial malignancy diagnosis, or asynchronous if they arise later [5].

Since its inclusion in the classification of monoclonal gammopathy (MG), smoldering multiple myeloma (SMM) has emerged as a significant aspect of MG [6], attracting attention in various clinical investigations.

Currently, no established strategies exist for treating or monitoring patients with myeloproliferative neoplasms (MPNs) and concurrent SMM. Additionally, the precise source of SMM in patients with MPN is not well understood, and there is uncertainty regarding whether an aberrant plasma cell condition arises from the identical hematopoietic clone as the MPN.

Numerous case reports have highlighted the occurrence of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) in patients with MPN, with details from only a limited number of patient cohorts published [7]. Remarkably, to date, there have been no reported instances of the concurrent diagnosis of essential thrombocythemia (ET) and SMM. In this report, we present a case of synchronous concurrent SMM and ET and provide a comprehensive review of the existing literature.

Case Presentation

An 82-year-old man with a history of hypertension and diabetes was referred to our department for the management of thrombocytosis. Physical examination revealed no remarkable findings, and there was no evidence of lymphadenopathy or hepatosplenomegaly. Laboratory results indicated a platelet count of 946 g/L, hemoglobin of 12.5 g/dL, and a white blood cell count of 6.4 g/L. The patient had no systemic symptoms.

Thrombocytosis workup was initiated, initially excluding infections and iron deficiency. The platelet count was notably elevated, suggesting uncommonly high levels for secondary causes of thrombocytosis.

The patient’s chemistry panel results are shown in Table 1. Monoclonal protein was measured at 36.6 g/L. Serum immunofixation electrophoresis revealed IgG lambda gammopathy. Free light chain lambda was elevated, and kappa was normal.