Category Archives: Research

Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

Posted on by
Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

Read more

Significant Steps Forward in the Understanding and Treatment of MPNs

Posted on by

Raajit Rampal, MD, PhD

February 13, 2024

Raajit K. Rampal, MD, PhD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, discusses some of the key takeaways from the 2023 American Society of Hematology (ASH) Annual Meeting and what he believes holds promise for the space in 2024.

This past year marked significant progress in the field of myeloproliferative neoplasms (MPNs) and highlights were presented at ASH 2023. Notably, 2 phase 3 trials were completed and 2 combination agents showed promising results. Additionally, several new non-JAK inhibitor drugs were highlighted, along with advancements in mastocytosis research.

Rampal explains that there is now excitement surrounding the emergence of small molecule inhibitors in clinical trials, which may offer potential insights. Moreover, the introduction of the first antibodies, particularly calreticulin antibodies from various companies, into clinical trials is anticipated to have a major impact, with insights expected to emerge soon.

These developments represent a significant step forward in the understanding and treatment of MPNs, offering hope for improved outcomes for patients in the near future.

Read more

Gut Microbiota Differs in Patients With MPNs

Posted on by

Ashley Chan

he gut microbiota in patients with myeloproliferative neoplasms (MPNs) showed a significant difference compared with healthy controls (HCs), according to a study published in the European Journal of Haematology, although patients with MPNs who have a specific driver mutation had a similar bacterial composition compared with HCs.

In particular, MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), pre-fibrotic myelofibrosis (pre-PMF) and primary myelofibrosis, have driver mutations, such as JAK2V617F, JAK2 exon, MPL or Calreticulin (CALR). Researchers found that patients with MPNs who are CALR-positive had the highest resemblance to HCs.

The study demonstrated that patients with MPNs have changes in the gut microbiota, which may be caused by their disease, which may include inflammation. This change in the microbiota has been shown to initiate and progress the disease, according to the study. Researchers also noted that the gut microbiota also affects the immune system, infection control and steady production of blood cells.

Read more

Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms

Posted on by

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.

Read more

 

CD123 As a Therapeutic Target in Accelerated and Blast Phase Myeloproliferative Neoplasms (MPNs)

Posted on by

Melissa A. Babcook MD, PhD, Gerard Lozanski, MD, Sarah A. Wall MD, MPH

Background

CD123 expression in MPNs has been reported in case series and targeted in one phase I study of patients with chronic phase MPN. We describe the clinical phenotype of patients with accelerated (AP) or blast phase (BP) MPNs paired with CD123 co-expression on CD45(dim) myeloid blasts.

Methods

Subjects were identified by diagnosis in the Ohio State University Comprehensive Cancer Center Leukemia Tissue Bank (OSUCCC-LTB). Clinical data were collected by retrospective chart review with IRB approval. CD123 expression was measured by immunophenotyping of cryopreserved peripheral blood (PB) or marrow (BM) samples. Blasts were identified by CD45(dim) gating and co-expression of CD7/13/33/34/117/123 was measured. CD123 expression was stratified by quartile and correlation with clinical characteristics measured by Chi-square test.

Results

41 PB or BM samples from 24 subjects were identified from the OSUCCC-LTB. Nine subjects had paired PB and BM specimens, 6 had samples obtained at multiple timepoints. Median age at sample collection was 65.8 years (range 35.2-79.7) and median time from diagnosis was 13.1 months (range 0-96.5). Constitutional symptoms were present at collection for 24 samples (58.5%) and splenomegaly present for 20 samples (51.3%). At sample collection, 19.5% had never received treatment, 19.5% had been previously treated, and 61% were currently on treatment, most (n=16, 64%) with JAK inhibitor. 19 samples were obtained in chronic phase (46.3%), 9 in AP (22.0%), and 13 in BP (31.7%). 16 samples (39.0%) were from transfusion-dependent patients, most (68.8%) for both red blood cell and platelets. Median PB blasts were 3.2% (range:0-76) and BM blasts were 3% (range 0-82) by morphology. Molecular sequencing and karyotype were available for 18 (43.9%) and 27 (65.9%), respectively. The most common mutations identified were JAK2 (50%), ASXL1 (27.8%), SRSF2 (22.2%), CALR (16.7%), and TP53 (16.7%). Normal karyotype was found in 37%, 33.3% had complex karyotype, 11.1% had del 5q or 7q/-7, and 18.5% had del 13q or 20q. CD123 expression on the CD45-gated blasts ranged from 0.3-95.6% with a median value of 11.02%. CD123 expression is shown in figure 1. Figure 2a shows correlation between CD123 expression and disease phase (p < 0.01). Figure 2b shows CD123 expression correlation with ASXL1 mutation status (p =0.023). There were no statistically significant associations between CD123 expression and any other tested variables.

Conclusions

These data support a clinical trial targeting CD123 in high risk MPNs, defined by blasts >10% or the presence of ASXL1 mutation, an important subpopulation of patients in need of more effective and less toxic therapy than current standards of care that typically include cytotoxic chemotherapy.

Read more

Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study

Posted on by

James T. England, Natasha Szuber, Shireen Sirhan, Tom Dunne, Sonia Cerquozzi, Madeleine Hill, Pierre J. A. Villeneuve, Jenny M. Ho, et al.

Abstract

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

Read more

NIH Analysis Reveals Rising Use of Complementary Health Approaches

Posted on by

February 6, 2024

An analysis conducted by the National Institutes of Health’s National Center for Complementary and Integrative Health (NCCIH) reveals a substantial increase in the overall use of complementary health approaches by American adults from 2002 to 2022.

The study, published in the Journal of the American Medical Association, highlights a surge in the adoption of complementary health approaches for pain management over the same period.

Researchers utilized data from the 2002, 2012, and 2022 National Health Interview Survey (NHIS) to evaluate changes in the use of seven complementary health approaches, including yoga, meditation, massage therapy, chiropractic care, acupuncture, naturopathy, and guided imagery/progressive muscle relaxation.

The key findings include:

  • The percentage of individuals who reported using at least one of the seven approaches increased from 19.2% in 2002 to 36.7% in 2022.
  • The use of yoga, meditation, and massage therapy experienced the most significant growth from 2002 to 2022.
  • Use of yoga increased from 5% in 2002 to 15.8% in 2022.
  • Meditation became the most used approach in 2022, with an increase from 7.5% in 2002 to 17.3% in 2022.
  • Acupuncture, increasingly covered by insurance, saw an increase from 1% in 2002 to 2.2% in 2022.
  • Additionally, the analysis showed a notable rise in the proportion of U.S. adults using complementary health approaches specifically for pain management. Among participants using any of the complementary health approaches, the percentage reporting use for pain management increased from 42.3% in 2002 to 49.2% in 2022.

Despite the findings, the authors acknowledge study limitations, including decreasing NHIS response rates over time, possible recall bias, cross-sectional data, and differences in survey wording.

The study also highlights the role of factors such as higher quality research supporting the efficacy of complementary health approaches, the inclusion of these approaches in clinical practice guidelines for pain, and the expanded insurance coverage for approaches such as acupuncture, which has contributed to increased patient access.

Read more

Myeloid Neoplasms: Better Understanding of their Molecular Pathogenesis with Improvised Genomic Testing: A Ray of Hope for Better Clinical Outcomes

Posted on by

With the increase in incidence and prevalence of myeloid neoplasms in India, it has become a necessity to understand its molecular mechanisms, acquisition of genomic alterations, and understand its primary and secondary resistance pathways which ultimately impact the decision of therapeutics. The objective of this review is to investigate the molecular aspects of this disease type and identify the biomarkers that help with diagnosis, risk assessment, prognosis, and selecting the best line of treatment for a speci icmyeloid neoplasm. Advancements and innovations in molecular technologies from simplest Real-Time PCR to high throughput next-generation sequencing have played a vital role in screening the most common mutations and fusions to the novel and rare. Molecular technologies have helped to enumerate the genomic landscape of myeloid malignancies. The understanding of both- the mechanisms and the technology is a strong combination as it has helped revolutionize precision oncology and helped in giving better therapeutic choices with better clinical outcomes. The importance of cellular morphology, clinical symptoms, and molecular pathology in assessing the risk of myeloid malignancies is emphasized and summarized in the review. The review concludes that understanding molecular pathogenesis can be improved by using clinical-pathological-molecular strategies for diagnosis and therapy decision-making.

Read more

Understanding Philadelphia Chromosome-Negative Myeloproliferative Neoplasms in Young Patients: A Comprehensive Study

Posted on by
By Mason Walker
Published Feb 6, 2024

Insights into Philadelphia Chromosome-Negative Myeloproliferative Neoplasms in Young Patients

Myeloproliferative neoplasms (MPNs) are a group of diseases in which the bone marrow makes too many red blood cells, white blood cells, or platelets. A recent study involving 609 patients diagnosed with Philadelphia chromosome-negative MPNs at the age of 45 or younger has brought new insights into the understanding of these diseases in younger patients.

Demographics, Clinical Variables, and Management Strategies

The study reported a variety of demographic, clinical, and laboratory variables, as well as the management strategies used for these patients. The majority of patients were diagnosed with essential thrombocythemia (ET) and polycythemia vera (PV). The median follow-up for the cohort was 9.1 years, and germline testing for hereditary MPN was not available.

The Association of Driver Mutation Variant Allele Frequency and Next-Generation Sequencing

The study also investigated the association of driver mutation variant allele frequency (VAF) and next-generation sequencing (NGS) with disease outcomes. This is important as these factors can play a significant role in the progression and management of MPNs.

Read more

Abstract WP249: Risk for Ischemic and Hemorrhagic Stroke is Increased in Veterans Exposed to Agent Orange and Those With Myeloproliferative Neoplasms

Posted on by
Natasha Mathur, Andrew Tiu, Zoe McKinnell, Puneet Gill, Martha Antonio, Shanshan Liu, Guoqing Diao, Ramesh Subrahmanyam, Craig M Kessler and Maneesh R Jain

Abstract

Agent Orange (AO) is a dioxin containing defoliant and carcinogen used in the Korean and Vietnam War. There is limited evidence of the association between AO exposure among Veterans and stroke. Stroke is not yet part of the list of presumptive conditions according to the Promise to Address Comprehensive Toxics (PACT) Act which provides Veterans and their survivors disability compensation for conditions arising from exposure to AO. Myeloproliferative Neoplasms (MPN) are uncommon etiologies of stroke but whether AO exposure increases incidence of stroke in MPN has not been described.

Utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database, a case-control study was performed from 1/1/2006 – 1/26/2023 on the Veterans from Illinois, the state most representative of the US population. ICD-9 and -10 codes identified Veterans with stroke and MPN. AO exposure was verified on the Veterans’ service duration and location. Qualitative data were compared by chi-square tests.

Among 586,555 Veterans from Illinois, there were 15,455 ischemic stroke (IS), 1,593 hemorrhagic stroke (HS), 2,752 MPN, and 59,393 with AO exposure. Among MPNs, there were 237 IS (41 with AO) and 26 HS (3 with AO). IS and HS were associated with AO exposure, OR 1.34 95% CI 1.28-1.41, p<0.0001, and OR 1.20 95% CI 1.03-1.39, p=0.02, respectively. MPN is associated with IS and HS, OR 3.52, 95% CI 3.08-4.03, and OR 3.54, 95% CI 2.4-5.23, both p<0.0001, respectively. There is no significant association with AO exposure among Veterans with MPN with stroke. Among non-MPN Veterans with AO exposure, there was an earlier median age of IS and HS, 67 vs. 70 and 67 vs. 71, both p<0.0001. There was no difference in median age of stroke among MPN Veterans with or without AO exposure. There were no differences with rates of hypertension, hyperlipidemia, diabetes, smoking, heart failure, and pulmonary hypertension among MPN Veterans with stroke with and without AO exposure.

In conclusion, there is an association of AO exposure with IS and HS with an earlier onset among those exposed. There is a strong association between MPN and stroke independent of AO exposure. The biologic plausibility of endothelial dysfunction and accelerated atherosclerosis from AO exposure warrants further investigation.

Read more