Stories about: blood disorders

Zeroing in on the fetal-to-adult hemoglobin switch and a new way to combat sickle cell disease

Normal red blood cell vs. sickle-shaped blood cell, which is found in sickle cell disease
Normal red blood cell vs. sickle-shaped blood cell.

It’s been known for more than 40 years that in rare individuals, lingering production of the fetal form of hemoglobin — the oxygen-transporting protein found in red blood cells — can reduce the severity of certain inherited blood disorders, most notably sickle cell disease and thalassemia. Typically, however, a protein called BCL11A switches off fetal hemoglobin production past infancy, but exactly how this happens has not been well understood until now.

In a new paper in Cell, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have revealed how BCL11A controls the switch in the body’s production of fetal hemoglobin to adult hemoglobin. It does so by binding to a DNA sequence — made up of the bases T-G-A-C-C-A — that lies just in front of the fetal hemoglobin genes.

Another approach to curing sickle cell disease is already being evaluated in a new clinical trial at Dana-Farber/Boston Children’s. The novel gene therapy restores fetal hemoglobin production by genetically suppressing BCL11A, which prevents it from blocking fetal hemoglobin production. Learn more.

“Genetically modifying this TGACCA segment could be another possible strategy to cure sickle cell disease by blocking BCL11A’s ability to bind to this DNA site and switch off fetal hemoglobin production,” says Stuart Orkin, MD, senior author on the study.

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A breakthrough in our understanding of how red blood cells develop

Artist's rendering of red blood cells
Red blood cells.

By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.

For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.

Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.

Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.

Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.

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Teaching an old drug a new trick to treat an ultra-rare red-blood-cell disease

Failed sickle-cell drug learns a new trick: hereditary xerocytosis

The National Institutes of Health maintains a library of drugs, the Clinical Collection, that are safe for humans but failed in clinical trials or didn’t make it to the market for other reasons. These compounds, numbering 450 to date, are just sitting on the shelf, waiting for a researcher to identify a disease process they might treat.

Repurposing such drugs could potentially save the pharmaceutical industry time and money. Getting a new drug from R&D to market currently takes $2 to 3 billion and 13 to 15 years. In contrast, some estimate that repurposing a safe drug could cost just $300 million and take just 6.5 years.

Pfizer, one of the biggest pharma companies in the world, saw the appeal. It just launched SpringWorks Therapeutics, a mission-driven company dedicated to reviving shelved drugs to treat underserved diseases. In its pipeline are experimental therapies to treat four diseases that currently have no cure.

One of the earliest-stage candidates is senicapoc.

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“Vampires” may have been real people with this blood disorder

Mural of Vlad the Impaler, who was accused of being a vampire. Perhaps, instead, he suffered from a blood disorder called porphyria.Porphyrias, a group of eight known blood disorders, affect the body’s molecular machinery for making heme, which is a component of the oxygen-transporting protein, hemoglobin. When heme binds with iron, it gives blood its hallmark red color.

The different genetic variations that affect heme production give rise to different clinical presentations of porphyria — including one form that may be responsible for vampire folklore.

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Medical milestone: Making blood stem cells in the lab

blood stem cells
The gradation of pink-to-blue cells illustrates the transition from hemogenic endothelial cells to blood progenitor cells during normal embryonic blood development. Daley, Sugimura and colleagues recreated this process in the lab, then added genetic factors to produce a mix of blood stem and progenitor cells. (O’Reilly Science Art)

Pluripotent stem cells can make virtually every cell type in the body.  But until now, one type has remained elusive: blood stem cells, the source of our entire complement of blood cells.

Since human embryonic stem cells (ES cells) were isolated in 1998, scientists have tried to get them to make blood stem cells. In 2007, the first induced pluripotent stem (iPS) cells were made from human skin cells, and have since been used to generate multiple cell types, such as neurons and heart cells.

But no one has been able to make blood stem cells. A few have have been isolated, but they’re rare and can’t be made in enough numbers to be useful.

Now, the lab of George Daley, MD, PhD, part of Boston Children’s Stem Cell Research program as finally hit upon a way to create blood stem cells in quantity, reported today in Nature.

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Discovering a rare anemia in time to save an infant’s life

Illustration of the erythropoietin hormone. A newly-discovered genetic mutation, which switches one amino acid in EPO's structure, resulted in two cases of rare anemia.
An illustration showing the structure of a cell-signaling cytokine called erythropoietin (EPO). It has long been thought that when EPO binds with its receptor, EPOR, it functions like an on/off switch, triggering red blood cell production. New findings suggest that this process is more nuanced than previously thought; even slight variations to cytokines like EPO can cause disease.

While researching a rare blood disorder called Diamond-Blackfan anemia, scientists stumbled upon an even rarer anemia caused by a previously-unknown genetic mutation. During their investigation, the team of scientists — from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, the Broad Institute of Harvard and MIT and Yale University — had the relatively unusual opportunity to develop an “on-the-fly” therapy.

As they analyzed the genes of one boy who had died from the newly-discovered blood disorder, the team’s findings allowed them to help save the life of his infant sister, who was also born with the same genetic mutation. The results were recently reported in Cell.

“We had a unique opportunity here to do research, and turn it back to a patient right away,” says Vijay Sankaran, MD, PhD, the paper’s co-corresponding author and a principal investigator at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s incredibly rewarding to be able to bring research full circle to impact a patient’s life.”

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Stem cell workaround cracks open new leads in Diamond Blackfan anemia

Diamond Blackfan anemia iPS cells hematopoietic progenitor cells
Though not bona-fide stem cells, hematopoietic progenitor cells produce red blood cells when exposed to certain chemicals. Could some of these compounds lead to new drugs for Diamond Blackfan anemia?

Diamond Blackfan anemia (DBA) has long been a disease waiting for a cure. First described in 1938 by Louis K. Diamond, MD, of Boston Children’s Hospital and his mentor, Kenneth Blackfan, MD, the rare, severe blood disorder prevents the bone marrow from making enough red blood cells. It’s been linked to mutations affecting a variety of proteins in ribosomes, the cellular organelles that themselves build proteins. The first mutation was reported in 1999.

But scientists have been unable to connect the dots and turn that knowledge into new treatments for DBA. Steroids are still the mainstay of care, and they help only about half of patients. Some people eventually stop responding, and many are forced onto lifelong blood transfusions.

Researchers have tried for years to isolate and study patients’ blood stem cells, hoping to recapture the disease process and gather new therapeutic leads. Some blood stem cells have been isolated, but they’re very rare and can’t be replicated in enough numbers to be useful for research.

Induced pluripotent stem (iPS) cells, first created in 2006 from donor skin cells, seemed to raise new hope. They can theoretically generate virtually any specialized cell, allowing scientists model a patient’s disease in a dish and test potential drugs.

There’s been just one hitch. “People quickly ran into problems with blood,” says hematology researcher Sergei Doulatov, PhD. “iPS cells have been hard to instruct when it comes to making blood cells.”

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Rare blood disorder sideroblastic anemia slowly reveals its genetic secrets

congenital sideroblastic anemia
Regardless of the gene, all patients with sideroblastic anemia have sideroblasts: red blood cell precursors with abnormal iron deposits in mitochondria, shown here ringing the cell nucleus. (Paulo Henrique Orlandi Mourao/Wikimedia)

A decade ago, Brooks McMurray’s routine check-up was anything but routine. The suburban Boston boy’s spleen was enlarged. His red blood cell count was low and the cells were very small and very pale, which suggested a serious iron deficiency anemia. The family pediatrician referred McMurray, now a 19-year-old college freshman, to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

There hematologists discovered the boy had unexpectedly high iron levels. Together with pathologist Mark Fleming, MD, DPhil, they solved the mystery. McMurray has congenital sideroblastic anemia, an inherited blood disorder so rare that fewer than 1,000 cases have been reported worldwide. Iron was getting stuck in the wrong place in the precursor red blood cells developing in his bone marrow.

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger et al).

A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.

In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically.

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Tool helps interpret subtle DNA variants from genome-wide association studies

Genome-wide association studies are huge undertakings that compare the genomes of large populations. They can turn up thousands to tens of thousands of genetic variants associated with disease. But which GWAS variants really matter?

That question becomes exponentially harder when the variants lie in the vast stretches of DNA that don’t encode proteins, but instead have regulatory functions.

“It’s hard to know which hits are causal hits, and which are just going along for the ride,” says Vijay Sankaran, MD, PhD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and an associate member of the Broad Institute.

Reporting in Cell, Sankaran’s team and two other groups at the Broad Institute describe a new tool that can looks at hundreds of thousands of genetic elements at once to pinpoint variants that truly affect gene expression or function. Called the massively parallel reporter assay (MPRA), it could help reveal subtle genetic influences on diseases and traits.

In Sankaran’s case, the MPRA is helping him understand how common variants contribute to blood disorders in children. “Most of the common variation is just tuning genetic function,” he says. “Just slightly, not turning it on or off, but actually just tuning it like a dimmer switch.”

The above video explains how the assay works – via DNA “barcodes.” Read more on the Broad Institute’s blog, Broad Minded.

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