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.
Tag Archives: myeloproliferative neoplasms
Abstract WP249: Risk for Ischemic and Hemorrhagic Stroke is Increased in Veterans Exposed to Agent Orange and Those With Myeloproliferative Neoplasms
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.
Ambitious £4 million project to develop clinical platform for blood cancer prevention
4th Feb 2024 – Edward Pinches
Professor George Vassiliou from the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), University of Cambridge will spearhead the project, which focuses on myeloid blood cancers, a group of blood cancers that accounts for more than 11,000 deaths each year in the UK.
The blood cancers, which affect both the bone marrow and blood, include acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and rarer cancers like chronic myelomonocytic leukaemia (CMML).
Truong on the Rationale for Investigating ERK2 Substrate Binding Modalities in MPNs
Billy Truong, PhD candidate, Fox Chase Cancer Center, discusses the rationale for investigating the functions of ERK2 substrate binding modalities in myeloproliferative neoplasms (MPNs).
Truong and colleagues are conducting research investigating cell signaling programs that are altered in MPNs. Specifically, treatment resistance often arises from the activation of the MAPK pathway, Truong says. Approximately 85% of cancers have genetic modifications in proteins, especially in the RAS protein, which ultimately drive uncontrolled tumor cell proliferation, Truong explains.
Downstream of the MAPK pathway is the ERK2 protein, which is a common target of cancer therapies, Truong notes. However, drugs that target the kinase function of ERK2 are traditionally designed to be nonspecific and are therefore toxic to healthy cells expressing ERK2, Truong emphasizes. Accordingly, drug specificity remains an unmet need for patients with MPNs.
Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights
Abstract
Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements
by Tanvi Verma 1, Nikolaos Papadantonakis2, Deniz Peker Barclift1 and Linsheng Zhang
Simple Summary
Abstract
Dr Vincelette on MYC Expression in Myelofibrosis
Nicole D. Vincelette, PhD, postdoctoral fellow, Moffitt Cancer Center, discusses findings from a study investigating the role of MYC expression and S100A9-mediated inflammation in a subgroup of triple-negative myeloproliferative neoplasms (MPNs).
To determine how MYC expression drives MPNs, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, Vincelette and colleagues conducted a study in which they generated a mouse model that overexpresses MYC in the stem cell compartment. This analysis demonstrated that MYC overexpression was associated with the mice developing a myelofibrosis-like phenotype, which included anemia, atypical megakaryocytes, splenomegaly, bone marrow fibrosis, liver fibrosis, spleen fibrosis. The mice also experienced adverse clinical outcomes, such as reduced overall survival (OS), compared with wild-type mice, Vincelette says.
Since the MYC-overexpressed mice developed myelofibrosis, the next step of this research was to investigate how MYC drives myelofibrosis, Vincelette explains. Investigators performed single-cell RNA sequencing to compare the bone marrow cells from MYC-overexpressed and wild-type mice. MYC overexpression correlated with upregulation of the S100A9 protein, which contributes to inflammation and innate immunity, according to Vincelette. Therefore, MYC drives the development of myelofibrosis through S100A9-mediated chronic inflammation. To validate the role of S100A9 downstream of MYC in myelofibrosis, investigators created a mouse model with S100A9 knockout in the presence of MYC overexpression, Vincelette notes. The S100A9 knockout protected against the development of myelofibrosis phenotype in that mouse model, Vincelette emphasizes.
By generating a mouse model that overexpresses S100A9, investigators also determined that S100A9 overexpression alone contributes to the development of myelofibrosis phenotypes, Vincelette says. When investigators treated the MYC-overexpressing mice with the S100A9 inhibitor tasquinimod (ABR-215050), the agent only partially abrogated the myelofibrosis phenotype, meaning the mice had reduced atypical megakaryocytes and splenomegaly. Additionally, the mice developed anemia and no OS difference occurred between tasquinimod and vehicle treatment, potentially because of off-target drug effects, Vincelette concludes.
Three Key Relationships Bring New Drugs to the MPN Community
Byline: Ann Brazeau, CEO & Founder
MPN Advocacy and Education International prides itself on bringing the experts to the MPN Community to ensure they are receiving accurate and updated information about clinical trials, treatment options, quality of life issues, and everything that could affect them medically. It also brings biopharmaceutical companies together with the researchers/clinicians at all of their programs in an effort to inform both physician and patient who is doing what in the laboratories around the world that could bring a new drug to commercialization for their use.
These three relationships are critical to new drug development. Our Industry Partners’ research and development teams work tirelessly in their labs to find answers to perplexing questions myeloproliferative neoplasms present. The MPN specialists who give so much of their time to speak at our programs, spend hours in their labs and also see patients throughout each day to understand the complexities of MPNs and how to best treat each patient, and many participate in heading trials at their academic and medical institutions. Patients participate and commit to lengthy clinical trials to help discover what works and what doesn’t. Without them, drugs would not be developed or approved. Drugs have to be tested for safety and efficacy in patients. There is no way around this fact. Hats off to those who volunteer to participate in clinical trials in hopes that the drug may one day benefit others who have the same condition as theirs. Participation in a clinical trial is a major contribution to our society.
Learn more about MPN clinical trials
This intricate connection is the key to so many discoveries that have saved lives, cured the common headache, stopped seizures, and cured some cancers. While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. People living with a chronic disease, like an MPN, benefit enormously from the pipeline of medications brought to market by hard-working clinical researchers who design and carry out clinical trials that show promise after testing in animals.
Education is critical to the success of clinical trials and participation. If physicians that treat you are not aware of the numerous trials currently underway, is it your responsibility to share what you know? We would say yes. Our programs for physicians that treat MPN patients always includes updates about current trials to be sure they are made aware of every single trial in the MPN space. This information coupled with site locations and trial criteria are essential to connecting the patient to a specific trial.
In this era of individualized treatment protocols and combination therapies, which will eventually be widespread in not only MPNs but other disease areas, it would be a shame to miss opportunities where potentially good therapies might fall off the grid for lack of trial participants and trial sites due to already strained programs. With the robust activity in MPNs currently, the challenges accompany the gains. Thus, the relationships among the three groups is even more important.
MPN Advocacy and Education International understands the challenges experienced by all three entities. Each plays an integral role in bringing new drugs to the shelves and ultimately to patients. Researchers who participate in trials and see patients can be overwhelmed. Patients may have financial issues that prohibit a commitment to a trial even if they want to participate. There are social and cultural factors that have historically left many trials with one demographic of participants, namely white, insured, and often retired.
The good news is organizations and our partners want to understand the challenges and want to help in all ways. In the seventeen years I’ve been working in MPNs, I am seeing the fruits of our advocating and educational efforts not only for patients, but in our relationships with biopharmaceutical companies and the hundreds of physicians who are not necessarily MPN specialists that see MPN patients. Our engagement and desire to grow a deeper understanding of the many challenges patients face has created a real interest in finding ways to close the gaps in areas of access, participation, education, and support.
Without collaboration and communication, the momentum needed for new drug development would quickly lose steam. MPN Advocacy and Education International remains committed to providing a platform for the dialogue necessary to keep the wheels in motion.
View our MPN Clinical Trials 101 Webinar
MPN Specialists Videos
MPN Advocacy & Education International partnered with MPN specialists to offer insights on patient concerns and updates on drug treatments during this pandemic. The videos are now available on our YouTube channel, click here to subscribe.
These videos are made possible by a grant from Bristol Myers Squibb
Naveen Pemmaraju, MD-MD Anderson Cancer Center
Mark Heaney, MD, PhD-Columbia University Medical Center
Ellen Ritchie, MD-Weill Cornell Medicine
Linda Smith-Resar, MD-Johns Hopkins
Dr. Resar’s presentation will be posted as soon as it is available.
One Patient’s Point of View on “Living” with Myelofibrosis
David told his story at the Cleveland MPN Patient Program in November
On a beautiful fall day in late August 2013, I received a call that changed the course of my life. The voice on the other end told me that they had reviewed my blood counts and determined that I had some sort of leukemia. They had pre-admitted me to the local hospital to meet an oncologist and have the necessary tests. After about two weeks I received my diagnosis of Primary Myelofibrosis, Intermediate 1. I was told that treatment options were limited and the only true cure was allogeneic bone marrow transplan
It is tempting to focus all our energies on our hope in medical interventions. But diagnosis brings fear, denial, anger, & depression. These impact your relationships and can throw you into a downward spiral. Being diagnosed with a life-threatening disease like an MPN is an existential challenge. It raises all the questions: Why are we here? What is life about? What lies beyond this life? How you answer these questions will affect how you deal with your disease and its physical effects.
We are all tempted to be sad and maybe even angry. But you do not have to give in to the negative. You can choose to respond with a positive attitude.
My diagnosis has changed the course of my life – but for the better. Because of myelofibrosis, I realized that I was spending far too much of my time and energy focused on some sort of future achievement. I was super-busy every day and the days passed in a blur. But myelofibrosis woke me up to the truth that life is not about some future achievement. Life is about today. Since my diagnosis, I have come to have a heightened enjoyment of the simple pleasures of daily living.
These last six years have been wonderful and I have enjoyed them more because of my disease. My son and his wife have been kind enough to give us two new grandchildren in the past four years – and I am making the most of that. I’ve made many good friends in the MPN community. I took up motorcycle riding. The more aware I am of my mortality – the more I savor every experience of life.
Your life only comes one day at a time. Today is the day you have – make it into something good. Refuse to let an uncertain future rob you of today’s joys.
David shared his story in the MPN Community Connection Newsletter click here to view
David is the support group coordinator for the northern Pennsylvania/Ohio area, if you are interested in participating you can contact us for more information. Click here to contact us.