Science & Medicine

My old flame — MPN and persistent fatigue

 * The surprising origins of MPN     

 * From PV to MF — one deadly mutation.

 * Inflammation and persistent fatigue.

*We could use some mercy now

* The surprising early origins of MPN.

In the past 18 months we’ve all been witness to a master class in mutation.

We watched as the lowly corona virus has rapidly adjusted its spike protein to improved its access to human cells. Simultaneously it shuffled a few of its 30,000 RNA nucleotides  to avoid some of our antibodies.  Even though it mutates at a relatively sluggish rate, each covid virus potentially mutates as it divides,   it doesn’t matter that 99% of the 12,000 or so covid  mutations already identified are irrelevant or even self-destructive. Successful mutations immediately acquire a competitive advantage  and dominate a surge simply because they work, they’re effective, they infect and divide.  Witness the Delta virus.

And so it is with the mutations driving myeloproliferative neoplasm.  On average we have about 3×1013 red blood cells , each with a lifespan of four months or so.  About 100 million new red blood cells are being formed in our body every minute.  Creation of new cells requires reading out, transcribing and translating long sequences of DNA with the likelihood of a misplaced letter here and there. Proofreading the final product is rarely perfect.

,One misplaced letter that is most significant to us is the transposition of a V or valine for an F phenylalanine in the 617 area of the Janus kinase gene. Result:  the creation of a new JAK2 protein, the JAK V617F stimulating blood production.  This mutation has a competive advantage over the wild type JAK2 gene….and so it proliferates.

The surprising news is the latency period.  How long dies  it take for the MPN phenotype — ET, PV, MF —  to emerge and be diagnosed?

 MPN has long been viewed as a disease of the older populations.  Although MPNs can be triggered by environmental stress events like radiation,   its origins are frequently in the womb, months before birth.  In many cases before the seventh year of life only surfacing 30 or 40 years later.  This replicated finding strongly suggests the need for very early diagnosis.

Significant new papers on the molecular genetics of MPNs by leading researchers like Ann Mullally,  Jacob Grinfeld,  Jyoti Nangalia, and John Mascarenhas confirm this early acquisition of the JAK2 mutation and help place this one mutation at the heart of MPN disease. Additional driver mutations acquired along the way determine which of  MPN phenotype will ultimately emerge.

And the critical role of JAK2-V617F:  “In clinical practice, MPN clone size can be approximated by the peripheral blood JAK2-V617F variant allele frequency(VAF), which reflects the fraction of nucleated blood cells that harbor the mutation but does not measure the contribution from anucleated mature red blood cells and platelets. (Steensma,2006).

Single-cell analysis demonstrates that the peripheral blood samples consistently underestimates the degree to which JAK2 mutant cells contribute to steady-state erythropoiesis . Indeed, the large fraction of JAK2-V617F mutant erythroid progenitor cells in individuals with PV (79% to more than 95%) suggests that nearly all erythropoiesis arises fromthe JAK2-V617F clone. ‘

To dig a bit deeper into the molecular genetics that are opening a new chapter in MPN diagnostics and treatment, here are four recent game-changing studies:

Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms,,Van Egeren et al., 2021, Cell Stem Cell 

Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution, Williams, et. al, 2020. BioRXiv

The Molecular Genetics of Myeloproliferative Neoplasms, Marneth and Mullally, Cold Springs Harbor Perspectives

Implications of Mutation Profiling in Myeloid Malignancies, Tremblay et. al., Oncologyl

* From PV to MF — one deadly mutation.

Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation ( Straube et al., Blood,)

“Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). …Mutational cooperation between Jak2V617F expression and Dnmt3a loss  drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo,  (CRISPR Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC,…  Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen [emphasis added]. ….Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a−/− Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer–driven inflammatory signaling.”

* My Old Flame:   Inflammation, aging and persistent fatigue.

An NIH-funded Mayo Clinic study sheds some light on why MPNs generally emerge in older populations..and suggest a class of drugs, Senolytics, that might be effective in relieving our worst symptoms. That study may help open a pathway to reolve the sources of persistent fatigue described in an earlier work.

Front Behav Neurosci. 2018; 12: 78.

.The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure (Front Behav Neurosci. 2018; 12: 78.)

The reduction of inflammatory cytokines may be an effective approach to relieve persistent fatigue.

Cell senescence, a common cause of chronic inflammation, is implicated in the aging process as well. Some well studied and commonly available substances — including dasatinib and some anti-oxidants — were shown to reverse these effects and extend lifespan. 

Many normal cells continuously grow, die, and replicate. Cell senescence is a process in which cells lose function, including the ability to divide and replicate, but are resistant to cell death. Such cells have been shown to affect neighboring ones because they secrete several pro-inflammatory and tissue remodeling molecules. Senescent cells increase in many tissues with aging; they also occur in organs associated with many chronic diseases and after radiation or chemotherapy. NIH

“A research team led by James L. Kirkland, M.D., Ph.D., of the Mayo Clinic in Rochester, Minnesota found that injecting even a small number of senescent cells into young, healthy mice causes damage that can result in physical dysfunction. The researchers also found that treatment with a combination of dasatinib and quercetin could prevent cell damage, delay physical dysfunction, and, when used in naturally aging mice, extend their lifespan.” 

Dasatinb, currently approved for application in Chronic Myeloid Leukemia, in combination with quercetin, or fisetin, naturally occurring anti-oxidants that neutralize free radicals, were successfully used in combination in the research.

 “Cell senescence has been suggested to be a major biological driver of age-related dysfunction and morbidity as well as exacerbating disease states…. These pro-aging effects are due to in large part to a complex secretome that contais inflammatory cytokines and chemokines, etc collectively known as the senescence-associated secretory phenotype (SASP).   Although beneficial under acute stress or injury the persistent SASP that occurs as a result of senescent cell accumulation in older adults leads to chronic inflammation which may be pathogenic for multiple age-related diseases…   SCIENCE review, 7/16/21. P. 281

To determine whether senescent cells caused physical dysfunction, the researchers first injected young (four-month-old) mice with either senescent (SEN) cells or non-senescent control (CON) cells. As early as two weeks after transplantation, the SEN mice showed impaired physical function as determined by maximum walking speed, muscle strength, physical endurance, daily activity, food intake, and body weight. In addition, the researchers saw increased numbers of senescent cells, beyond what was injected, suggesting a propagation of the senescence effect into neighboring cells.

Finally, the researchers found that treating very old (24- to 27-month-old) mice with D+Q biweekly led to a 36 percent higher average post-treatment life span and lower mortality hazard than control mice. This indicates that senolytics can reduce risk of death in old mice.

* Wotta Week — We could use some mercy now … In a week that saw the catastrophic effects of the  US withdrawal from Afghanistan,  a fourth more virulent wave of Covid-19 via the Delta,  the Haitian earthquake and publication of  the IPCC Climate Report confirming the irreversible rise of sea levels amid reports of worldwide fires, floods, hurricane,  and killing heat waves,  we figured (1) WE ALL COULD USE SOME MERCY NOW, as well as (2) a note of cheer from Annie Staninec and a couple of kids.  See ‘ya.

(And in case all that doesn’t work, here’s a full Stanford University class with Dr. Robert Sapolsky that will at least help us sort through the biology and physical roots of our well earned depression.)


Thank you!

With special thanks to Carlos Garces,  Helen Iden,  Jeremy Smith, Avraham Dworsky, Trisha Margeson, Howard Selinger, Mary Cotter and, of course, Ellen Jacquart for continuing  support of MPNforum publications.

Looking for something?

The Labor Day 2021 Worldwide  LIST of HEMATOLOGISTS ... Now 416 names compiled from Patient input by Ellen Jacquart.

To get to the MPNforum Magazine iSummertime 2021 Issue with the MPN Symptom Assessment form, and Dr.Nicolaus Krogers paper on Survival Odds after Stem Cell Transplant plus links to the full MPN Clinic Index and Responses, and Catalog of articles  go HERE.

The current issue of the MPN Quarterly Journal has much more on the mutations affecting us.

And head here for the the COVID/MPN Special Report,

For a quick check up on your own progress, there’s both the MPN Symptom Assessment Form and the Myelofibrosis prognostic scoring tests on the MPN MAGIC site.

You can always find Back Articles and Issue Covers with links at The Catalog page:

If you’re really stuck go to Google, type in MPNforum: followed by a description of what you’re searching for.  Or write us at ourMPNforum@gmail.com. Always good to hear from you.

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