Tag: AML

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.”

/ Margaret / 1 Comment

Remember the post I wrote back in December 2014 about myeloma subpopulations and the bone marrow microenvironment? Probably not…so here’s the link: http://margaret.healthblogs.org/good-or-bad-for-myeloma/first-do-no-harm-myeloma-subpopulations/

The main point is that not much is known about the interactions between the myeloma subpopulations living in our bone marrow, how they compete for survival and so on…

Therefore, the only conclusion, in my opinion, is that going in with conventional bombs and blasting the heck out of this microenvironment doesn’t seem to be the best strategy for those of us with MGUS and SMM…certainly not until we know a LOT more about what goes on inside this complex and, I would add, delicate setting.

Luckily, there have been more studies on this topic since my 2014 post, including this recent Dana Farber one, titled “The bone-marrow niche in MDS and MGUS: implications for AML and MM.” A blog reader sent me the link (thanks!): goo.gl/Ew3K4A

The full study isn’t available for free online, but I was able to read it thanks to a good friend. Okay, let’s have a look at it…

We know that MM is preceded by MGUS and by an intermediate stage called SMM.

Progression, that is, the “clonal evolution” of myeloma, takes place between MGUS and MM. But, the researchers add, some of the characteristics of myeloma can be found, “at lower frequencies,” at the MGUS and SMM stages. For example, the gene deletions.

Therefore, they say, it is the development of neoplastic “subclones” in the earlier stages that probably leads to the progression to myeloma.

This development wouldn’t be able to take place without the help of the bone marrow microenvironment, which therefore must be targeted in order to prevent progression as well as increase the effectiveness of conventional treatments once the stage of MM has been reached.

As I was reading this study, full of technical jargon that I could barely grasp, I began imagining the bone marrow microenvironment as a marketplace where strong nasty myeloma hooligans live and operate in coexistence with other, not-so-harmful, silly myeloma characters, as well as a bunch of normal folks, our normal cells.

Problem: myeloma clones have the ability of turning the marketplace into a toxic environment that helps them grow and proliferate.

A lot depends on how the marketplace reacts to these attempted changes. If it is weak and yields to the MM hooligans, it will become full of “weeds.” If it resists, it will be full (well, perhaps not entirely!) of crowds of happy customers, what the researchers call a “physiologically useful crop of mature blood cells,” that is, normal blood cells.

Now, a NORMAL marketplace contains all sorts of custome…I mean, all sorts of cells, including osteoclasts, macrophages, endothelial cells and, don’t you love this one?, sympathetic neurons. Lots of different cells that live happily ever after in this lovely area of the body.

Too many details here…okay, we don’t need to know this stuff…skip skip skip.

Certain cells (the above-mentioned stromal cells, e.g., after they have gone over to the dark side) become responsible for helping myeloma develop. Furthermore, whenever myeloma cells initiate a disruption, things that should be sleeping (in technical terms: in a quiescent state) wake up (remember EBV?). Not good.

Disruptions also cause tumor suppressor genes, such as Rb1, to be…suppressed. Also not good!

The end result of all the disrupting and suppressing, without any reaction from the immune system, is that the BM microenvironment becomes myeloma-friendly, and MM stem cells can begin proliferating, helped along by processes such as angiogenesis (remember all my posts on VEGF?).

As you can imagine, the study doesn’t mention anything remotely non-conventional. But some of its findings are interesting, so let’s keep reading.

Ah, another thing occurs: immunosuppressive cells arrive in the marketplace and make such a ruckus that T cells and B cells are completely overwhelmed and can’t function properly. This means, of course, that myeloma cells are no longer being sought and destroyed by our immune system.

The study therefore gives us a lesson in progression. First and foremost, as we’ve just seen, myeloma cells learn how to avoid being annihilated by the immune system. They then create what the researchers call an “immunosuppressive environment” where the immune system defenders are no longer able to function normally. Other types of important cells present in this now-toxic environment are also affected, such as stromal cells.

When MGUS progresses to SMM and then MM, immunosuppression is one of the main culprits. In fact, I recently read a study that discussed this problem, concluding that patients with SMM whose other immunoglobulins—in my case, e.g., IgA and IgM—are suppressed are more at risk of developing myeloma. *

The questions are: can we stop this process? How? And…when?

In 2014 (and before), my opinion was to “watch and wait” for as long as possible. Until CRAB symptoms appear. My opinion hasn’t changed in all these years. Indeed, it hasn’t changed today.

“Watch and wait” doesn’t mean sitting around and moping and doing nothing but watch TV series all day long. It means being proactive, doing research, enjoying life, taking something that doesn’t have any toxic side effects and that has been shown at least in vitro to be anti-myeloma, such as curcumin. And so on. There’s lots of stuff we can do in this stage…

Okay, I think this is enough for one day. After almost falling asleepzzz myself, I decided to divide this post into three parts…or perhaps only two.

So…more on this topic tomorrow! Ciao!

P.S. The study also discusses the evolution from MDS to AML, but I didn’t really look at that part, of course, since it’s not my main focus…

* P.P.S.S. While it’s true that my IgA and IgM are suppressed (barely “alive,” in fact!), it’s also true that they’ve been pretty much at the same tiny level for years now. So yes, I am in the high risk category BUT I am still here, leading a normal life, no CRAB symptoms…

Living proof that being at “high risk” doesn’t have to be as scary as it sounds…right?  🙂 

Leukemic cells transformed back into normal cells: could that be possible…some day?

/ Margaret / 3 Comments

I was fascinated and intrigued by almost everything I read in this New Yorker article written by Jerome Groopman who is, among other things, a hematologist: https://goo.gl/ (thanks for posting the link on FB, Don!) I’m going to re-read the article tomorrow…it contains so much food for thought, too much for just one session, in my opinion…but in the meantime I thought I’d post the link so that you can have a look, too, if you want…

The article focuses on the idea that some day we might be able to turn leukemic cells into normal, healthy red and white blood cells and platelets, using a drug that doesn’t kill everything in its path (= healthy cells as well as cancer cells) but that targets only the leukemic cells…without killing them! Mind boggling, isn’t it?

It’s impossible to list all the other interesting stuff that you can read about in this article — for example, the case studies described by Dr. Groopman…the section he devotes to pancreatic cancer and pancreatic cancer patients and the Notch gene (I’ve written some posts on the dastardly Notch mutation, which is important in myeloma, too…just do a Search of my blog for “Notch”). And, by the way, curcumin inhibits Notch…yep, it does. Again, search my blog…

Anyway, if you find yourself without anything good to read this weekend, click on the above link. You won’t be sorry, I’m sure!

Okay, I need to get back to work now. Ciao! 🙂

Two new AML stem cell killers

/ / 3 Comments

In my June 11 post I mentioned reading about two compounds that effectively eradicate AML at the bulk, progenitor and stem level: celastrol and 4-hydroxy-2-nonenal or HNE (AML stands for acute myelogenous leukaemia, by the way). Well, thanks to Sherlock Smiley face, I was able to read the whole University of Rochester/University of Pennsylvania study. The abstract can be seen here: http://tinyurl.com/6ltvw5

 

The full study begins with an acknowledgment of the importance of cancer stem cells, or CSCs, for studies of basic tumor biology and the development of improved therapies. Like normal stem cells, CSCs are thought to reside at the apex of a developmental hierarchy and are responsible for the continued growth and expansion of bulk tumor populations. Consequently, the biological activity of CSCs may contribute to initiation, maintenance, and relapse of at least some forms of cancer. Yes, this sounds all too familiar…

 

The researchers further comment that several studies have shown that AML stem cells (AML-SCs) are refractory to commonly used clinical agents such as cytarabine and anthracyclines, thereby further supporting the hypothesis that malignant stem cells represent a probable reservoir from which disease relapse may occur. In vitro studies, they continue, have shown that the combination of the chemotherapeutic drug idarubicin and the proteasome inhibitor MG-132 can effectively eradicate leukemia stem cells via a mechanism involving concomitant inhibition of nuclear factor-kB (NF-kB)–mediated survival signals and induction of oxidative stress.

 

Then they discuss parthenolide (PTL), a substance that can ablate AML-SCs as a single agent. As a single agent, mind you! Impressive. They add that the SC-killing mechanism is similar to the one used by the idarubicin and MG-132 mixture, and that is: combined inhibition of NF-kB and induction of oxidative stress, thus indicating that common biological principles underlie the anti–AML-SC effects of these agents despite their chemical diversity.

 

The researchers decided to explore other AML stem cell killing possibilities using gene expression signatures. They examined the natural antileukemia characteristics of PTL, which has been shown to induce very potent and specific effects, mediating rapid death of AML-SCs, but not normal hematopoietic stem and progenitor cells, looking for other substances that provoke a similar response in cancer stem cells. They then tested those compounds against AML stem cells.

 

For this purpose, they used the GEO or Gene Expression Omnibus, a sort of humongous gene expression warehouse. To their surprise, they found a recurring and chemically diverse group of compounds that mimic the PTL gene expression pattern and, like PTL, are capable of ablating AML cells at the bulk, progenitor, and stem-cell level. The sentence that follows is also important: As with PTL, the mechanism of action for these new compounds involves concomitant inhibition of the NF-kB survival signal and induction of oxidative stress, suggesting their general importance in targeting AML stem cells. Sorry to keep repeating “NF-kB plus oxidative stress,” but this is a crucial point, methinks.

 

The researchers identified and tested four compounds, including the two that I mentioned the other day and that inhibit NF-kB and proteasomes. These two were found to have molecular characteristics comparable to those of PTL. I should note that these compounds, while known for their anticancer activity and for their ability to inhibit NF-kB, had never before been tested for their specific ability to target leukemic stem cells.

 

By the way, the other two compounds, gedunin and hemin, did not target the AML stem cells and were therefore discarded.

 

In conclusion, this study is remarkable not only because of the discovery of two new compounds that exterminate AML stem cells, but also because a gene expression database was used to identify potentially useful compounds. Very very interesting approach…