Tag Archives: leukemia

Cancer: what’s Down syndrome got to do with it?

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A Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia.

A Wright’s stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia. {credit}VashiDonsk via Wikipedia{/credit}

Trisomy 21 (having 3 copies of chromosome 21) is most well known as the cause of Down syndrome. But as you can imagine, having an entire extra copy of a chromosome has other negative consequences as well. For one, people with Down syndrome are 20 times more  likely than the average person to develop a severe form of leukemia, B cell acute lymphoblastic leukemia (B-ALL). Two recent studies have helped further our understanding of the molecular disturbances that take place in trisomy 21.

In Nature, Audrey Letourneau et al. took advantage of a rare situation to identify the genes that are misregulated in Down syndrome. The researchers profiled the transcriptomes of identical twins that differed in one crucial aspect: one twin had 3 copies of chromosome 21, while the other had a normal complement of chromosomes. (The samples were collected post-mortem from the fetuses, with the permission of the parents). This approach allowed the researchers to avoid any noise from irrelevant differences, since the genes of both twins would be identical. (Read the article in The Scientist about this study here).

Not surprisingly, they found that trisomy 21 causes gene regulation problems on all chromosomes. Misregulated genes are organized along the chromosomes in domains, and these domains were defined by changes to the chromatin methylation patterns. Importantly for future research efforts, they also showed that the corresponding genomic regions in the mouse model for trisomy 21 were similarly modified compared to control mice.

In a second paper published online this week by Andrew Lane et al. in Nature Genetics looked specifically at the relationship between Down syndrome and B-ALL.  The authors identified two genomic events as the drivers behind Down syndrome-related B cell acute lymphoblastic leukemia (B-ALL): overexpression of the nucleosome remodeling protein HMGN1 and changes in histone methylation marks. (You can read the Dana-Farber Cancer Institute’s press release about the study here).

Through a very meticulous set of experiments, they first show that just having an extra copy of a small region of chromosome 21 (or in this case, the corresponding mouse chromosome, 16) with 31 genes is sufficient for giving B cell precursors the ability to self renew indefinitely—the first step to cancer formation. From there, they identify and confirm a single driver gene on chromosome 21, HMGN1, as being expressed at unusually high levels. This high expression of HMGN1 causes a decrease in one type of methylation (H3K27me3), leading to overexpression of genes usually carrying both H3K27me3 and another histone mark, H3K4me3.

Trisomy 21 karyotype. All the normal chromosomes + 1.

Trisomy 21 karyotype. All the normal chromosomes + 1. {credit}Wikipedia{/credit}

Interestingly, the authors of Letourneau et al. mention HMGN1 as a good candidate for regulating the genome-wide chromatin modifications they found. The accompanying News & Views article by Benjamin Pope and David Gilbert note that HMNG1 should be a target of future study in Down syndrome. Looks like the authors of Lane et al. got the message far in advance!

So a pattern emerges: changes in chromatin methylation patterns are a key event in trisomy 21 overall and in Down syndrome-associated B-ALL specifically. Dr. Lane, lead author of the paper in Nature Genetics  wonders “Could this [chromatin modifications] be a unifying theme for phenotypes (not only cancer) associated with DS?” As I mentioned earlier, having 3 copies of this chromosome is bad for a number of reasons: higher risk of B-ALL and testicular cancer, vision and hearing problems, thyroid issues, higher risk of type I diabetes, gastrointestinal issues, low or no fertility and the more widely known neurocognitive isssues. Future studies on epigenetic changes in Down syndrome, and the regualtion of HMNG1, should be able to unravel the mechanisms underlying these different aspects of Down syndrome.

Outside of Down syndrome, these 2 studies may also lead to a better understanding of (and hopefully new treatments for) cancers caused by epigenetic changes. As the article by Lane et al. showed, changes to the chromatin landscape allowed B cell precursors to make that first step toward leukemia. By understanding how this happens, we can start to find ways to prevent it.

In Memory of Dr Nicole Muller-Bérat Killman 1932-2014

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Guest post by Pooja Aggarwal
Publisher, Academic Journals, Nature Publishing Group.

"One of NPG’s longest-serving and most dedicated academic editors."

“One of NPG’s longest-serving and most dedicated academic editors.”

It was with great sadness and shock that I learnt of the death of Dr Nicole Muller-Bérat Killman, Editor-in-Chief for our journal Leukemia. Nicole died on February 23rd 2014 at the age of 82.

Few people know of Nicole’s clinical contributions to the field of leukemia. She performed one of the early HLA-haplotype mis-matched bone marrow transplants for severe combined immune deficiency (1978) and an early description of acute lymphoblastic leukemia with t(4;11).

Nicole along with her husband, Sven-Aage,  made a formidable duo working together in the laboratory to unravel the biology of acute leukemias and related disorders.  They spent three years with Prof. Eugene Cronkite and colleagues at the Brookhaven National Laboratory in the US.  Tritiated thymidine had just been discovered as a technique to label dividing cells and following their fate, Nicole and Sven-Aage were able to study the lifespan of hematopoietic cells in the laboratory and in humans.  Their reports on this subject are classics.

Next they returned to Denmark where Nicole worked in the State Serum Institute in Copenhagen as leader of the leukemia and transplantation laboratories.  Her main research interest was the use of in-vitro cultures of normal and leukemia cells to study biological questions, but she also collaborated with her husband on leukemia diagnosis.

In 1987, Nicole and Sven-Aage founded the journal Leukemia.  After Sven’s death Nicole returned to Paris (which she loved) to became Editor-in-Chief.  She tackled the job with great vigour, sometimes to the dismay of many authors and reviewers.  Nicole dedicated her life to Leukemia running what might be best termed a one woman show out of her Paris flat.

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Following ponatinib’s approval, leukemia drugs jockey to be first-line therapies

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Beth Galliart and her horse Austin{credit}Michelle Arani{/credit}

In June 2008, Beth Galliart was diagnosed with chronic myeloid leukemia. At the time, her doctors put her on Gleevec (imatinib), a small-molecule drug available since 2001 that is often touted as the poster child of personalized medicine. Marketed by Switzerland’s Novartis, Gleevec specifically targets the tyrosine kinase enzyme that is overactive in the white blood cells of people with leukemia. For close to nine months, the drug worked wonders for Galliart, and her blood counts returned to normal levels. But she soon started to feel tired again. A blood test confirmed that her cancer had returned.

Galliart’s doctors made a decision in March 2009 to switch her to Sprycel (dasatinib), a comparable tyrosine kinase inhibitor (TKI) from New York’s Bristol-Myers Squibb. She ended up taking that drug for only three days, though: her doctors took her off the drug when they received the results of a genetic test revealing that her cancer cells had evolved the T315I mutation in the tyrosine kinase BCR-ABL, making it impervious to all approved TKIs for the disease, including Gleevec and Sprycel. Galliart, an executive assistant at an investment firm in Silicon Valley, California, prepared herself for a risky bone marrow transplant. Her family prepared for the possibility that she might die.

Distant cousins from Kansas came to visit and say their final goodbyes. They and Galliart were picking strawberries one day in May 2009 when her phone rang. It was a clinical study coordinator from the University of California–San Francisco (UCSF) on the line. A managing partner from Galliart’s firm knew a UCSF doctor who was running a phase 1 clinical trial with an experimental agent called ponatinib. On the basis of preclinical work, this drug was thought to inhibit the mutated forms of the BCR-ABL protein that are responsible for people’s resistance to most TKIs—including the T315I mutation.

Galliart quickly enrolled in the study. A month later, she received her first dose of the drug.

Although she did suffer intense bone pain for three days after first receiving ponatinib—“It was sort of like a bomb was going off in my whole body,” recalls Galliart, 47—her cancerous blood cells have not come back since. She is now training for a half-marathon and regularly rides and jumps horses.

Fortunately, Galliart’s positive experience with ponatinib is not unique. In a phase 2 trial of 449 people with CML or the similar acute lymphoblastic leukemia (ALL) who were intolerant to other TKIs or who had a confirmed T315I mutation, around half responded favorably to the drug. The results were presented earlier this month at the American Society for Hematology meeting in Atlanta. Phase 1 trial results involving 81 participants, including Galliart, were published in late November in the New England Journal of Medicine (367, 2075–2088, 2012). Ponatinib was approved by the US Food and Drug Administration (FDA) today. It will be marketed by Ariad Pharmaceuticals of Cambridge, Massachusetts, as Iclusig.

“This drug has the potential to be a best-in-class agent that may be completely invulnerable to single-kinase-domain mutations,” says Neil Shah, the UCSF hematologist who treated Galliart. “I’m hopeful that it really will remove single-kinase-mutation–mediated resistance out of the picture.”

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Does a new treatment for leukemia herald a new era in drug discovery?

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Brent R. Stockwell, Ph.D. is an Associate Professor of Biological Sciences and of Chemistry at Columbia University, an Early Career Scientist of the Howard Hughes Medical Institute and author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, which was called “critical reading” by Robert Bazell, chief science correspondent at NBC News and “an absolute page-turner” that manages to “distill a complex, changing field into a beautifully written, well-crafted story” by Siddhartha Mukherjee, winner of the 2011 Pulitzer Prize for General Nonfiction.

Dr. Stockwell’s research involves the discovery of small molecules that can be used to understand and treat cancer and neurodegeneration. He has received numerous awards, including a Burroughs Wellcome Fund Career Award at the Scientific Interface, and a Beckman Young Investigator Award. He has published 59 scientific papers, is an inventor on 10 issued US patents, has given 60 invited presentations around the world, and has received 33 research grants for over $10 million. He co-founded the biopharmaceutical companies CombinatoRx (now Zalicus) and Solaris Therapeutics. You can follow him on Twitter at @bstockwell.

A few years back, a 75-year-old woman whom we will call Dorothy went to see her doctor and received a disturbing diagnosis: Dorothy had developed chronic lymphocytic leukemia (CLL), a type of cancer of the white blood cells. Hearing the words diagnosis and cancer together in the same sentence in your doctor’s office will likely induce a sense of fear and panic, before any mitigating factors seep into your consciousness. This fear alone may jeopardize your well-being, as has been remarked upon in a recent Soapbox Science blogpost by David Ropeik.

Dorothy was at the beginning of her disease course. Each patient’s cancer can be assigned a specific stage in its evolution from a single ill-behaved cell to a massive metastatic invader1. Dorothy was fortunate, if such a word is appropriate in this context, to have stage 0 CLL, which indicates merely an unusually large number of lymphocytes (white blood cells), but no other, more dangerous, manifestations of disease. Since cancers are better treated at early stages, this appeared to be good news, in a relative sense. Unlike more aggressive and rapidly fatal cancers such as pancreatic cancer, the clinical course of CLL is uncertain. One patient may live with the disease for decades without treatment, whereas others will rapidly develop a more advanced disease and need aggressive drug therapy, which may or may not be effective2. So, although Dorothy faced an uncertain future, all indications were that she should be optimistic.

Two years passed as Dorothy watched her leukemia, and in this time, it evolved to stage 1 CLL, manifesting as enlarged lymph nodes. Nine moths later, Dorothy’s health problems began to mount. She endured deep-vein thrombosis, a clotting of her veins, which caused a blockage in one of her arteries in her lungs. Three months later, in April of 2010, Dorothy came down with a weeklong fever and cough, and developed swelling of her legs and a general weariness, for which she was admitted to Montreal General Hospital3. Within days, Dorothy’s liver failed, and her mental health declined, as she faded from consciousness into a delirious state. Finally, 48 days after she was admitted to the hospital, and three years from her initial diagnosis, Dorothy succumbed to her disease.

With our burgeoning knowledge of cancer genetics and mechanisms, why is there no drug that could have slowed or reversed the course of Dorothy’s leukemia—is there any hope for the CLL patients of the future? An emerging trend in cancer therapeutics is the need for precise matching of drugs to disease subtypes—could one make a drug that is designed to address the unique networks and proteins found in CLL tumor cells? Such a tailor-made drug for CLL would likely have fewer side effects than the systemic, blunt chemotherapy this is commonly used to treat most cancers today. Moreover, such a customized drug would likely be more effective, by disabling the specific molecular defects found in CLL. This customization of drugs to diseases is an emerging challenge in cancer drug discovery, and indeed in all of medicine—how do we turn our increasingly sophisticated understanding of disease mechanisms into better therapies for patients?

Increasingly in this post-genomic era, our molecular understanding of disease leads us to a protein that appears to be an ideal candidate for attack with a drug. However, more often than not, these therapeutically and biologically attractive proteins are considered undruggable, resistant to modulation with small molecule drugs (most drug molecules are considered small compared to proteins, which are quite large on the scale of atoms).

Orally available drugs typically function by penetrating inside cells and tissues and directly attaching themselves to crucial proteins that regulate or cause disease. However, proteins vary tremendously in their susceptibility to drug-based attacks. A few proteins have large cavities or pockets that are perfectly suited to tightly enveloping small molecule drugs, whereas most proteins have relatively smooth and featureless surfaces, akin to the side of a sheer cliff, with no footholds for drug molecules. Indeed, all known drugs affect just 2% of human proteins, and most of the remaining proteins are considered challenging or impossible to target with small molecule drugs. Unfortunately, most disease-regulating and disease-causing proteins lie within this more challenging category of potential drug targets, suggesting it may not be possible to address the diseases controlled by these proteins.

The Bcl-2 family of proteins has been thought to represent such a class of challenging drug targets, because they function by interacting with other proteins, as most challenging proteins do. That is, their molecular function is to engage in a tight-fitting interaction across a large region of their surface with other proteins—a surface area much larger than a traditional drug molecule can cover. A grand challenge for chemists and biochemists is to create methods for disrupting these large protein-protein interactions. If it were possible to disrupt any protein-protein interaction of interest, potently and specifically, a wealth of new medicines would be within reach; these would likely be far more effective than out current drugs, and they could be targeted to each disease subtype to reduce systemic side effects, such as hair loss and nausea, that are so common with older, blunter drugs.

One approach that is emerging as effective for attacking protein-protein interactions with small molecules is fragment-based drug design. In this approach, pioneered by Stephen Fesik4, instead of throwing thousands of randomly chosen drug candidates at a target protein to find one that sticks, researchers break drug candidates down into smaller functional units, and test these fragments, as they are known, for their ability to interact with a specific protein. Fesik and his colleagues used this approach to design a molecule, piece by piece, that can specifically and potently interact with the Bcl-2 family of proteins that prevent apoptosis, a specific form of cell death that many tumor cells become resistant to5.

This approach appears to have born fruit: in December of 2011, it was reported in the Journal of Clinical Oncology that patients with CLL were particularly susceptible to treatment with the Fesik drug that targets the Bcl-2 family of proteins6. Bcl-2 family proteins play a pivotal and specific role in allowing CLL tumor cells to survive, as though their default state is death. In these specific tumor cells, Bcl-2 proteins serve as a critical switch that turns off their death program; blocking the Bcl-2 proteins with a small molecule drug can re-activate this death program.

 

Figure 1. Structure of the Bcl-2 protein (red, white and blue surface) bound to a portion of the Bax protein (grey balls and sticks). When these proteins are bound together as shown, CLL tumor cells can survive and grow.   

 

This Bcl-2 targeted drug represents new hope for CLL patients, such as Dorothy. However, the implications are even broader: an otherwise challenging set of proteins (Bcl-2 family proteins) has succumbed to a small molecule drug attack. There are more than 20,000 protein-coding human genes, and only 2% of these have been targeted with small molecule drugs. Perhaps we are seeing the beginning of the assault on the remaining proteins, untouched by drugs until now. If fragment-based screening and other emerging methods for tackling these difficult proteins are successful, we may see a renaissance in the coming decade in the fields of drug discovery and medicine.

Figure 2. Model of a small molecule inhibitor (ABT263, from Abbott Laboratories, grey balls and sticks) bound to Bcl-2 (white, red and blue surface), displacing the Bax protein. By disrupting the Bcl2-Bax protein-protein interaction, this small molecule drug candidate can initiate cell death in CLL tumor cells. Images generated by Miki Hayano and Gisun Park.

References

1. NCI. Stages of Chronic Lymphocytic Leukemia. National Cancer Institute;  [cited 1/18/2005]; Available from: https://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page2.

2. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(5):544-50.

3. Esfahani K, Gold P, Wakil S, Michel RP, Solymoss S. Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature. Curr Oncol. 2011;18(1):39-42. PMCID: 3031356.

4. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996;274(5292):1531-4.

5. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677-81.

6. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011.