Newsletter - Fall 2020

This episode is about a very important new publication by Dr. Lindsley’s group at the Dana-Farber Cancer institute. The title is “Clonal hematopoiesis in the inherited bone marrow failure syndromes”, published in the journal “Blood” in July 2020. Access the original article, here. There is also a second, more detailed article in the works, conducted in collaboration with the North American SDS Registry and Dr. Akiko Shimamura, which will hopefully be published very soon.

 

One of the biggest problems with Shwachman-Diamond Syndrome is that it puts patients at high risk for leukemia early in life, specifically Acute Myeloid Leukemia (AML) or a pre-leukemic condition called Myelodysplastic Syndrome (MDS). Once leukemia develops, it is very hard to treat. Currently, the only potential cure for leukemia is bone marrow /stem cell transplant, but this is most effective when done *before* full blown leukemia develops. It is a very difficult and long process, with a high risk of life threatening complications and side effects. A central challenge is to predict which patients will develop leukemia and when, so that a transplant can be initiated preemptively to give patients the best chance at survival.

 

This article presents a model for making this prediction by analyzing new acquired mutations in the blood forming cells of the bone marrow.

 

Normal bone marrow and blood

Our blood is produced and maintained throughout our lifetime by special cells in the bone marrow, called hematopoietic stem and progenitor cells (HSPCs). Let’s just call them stem cells. They can self-renew, make blood cells of different lineages (that is red cells, white cells, and platelets), and keep a balance of the right amount of each.

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SDS bone marrow: what are clones and what do they have to do with leukemia?

In SDS, these stem cells are less fit: they may die sooner, self-renew less efficiently, and produce fewer mature blood cells. SDS is caused by (biallelic germline) mutations in the SBDS gene in over 90% of patients. Over time, the stem cells can acquire new (somatic) mutations. Some of these mutations can make them more fit, and allow them to multiply to build up a clone. A clone is a group of cells that derive from a single stem cell with a growth advantage or increased fitness compared to its neighbors.

 

In SDS, there are two ways SBDS deficient stem cells can become more fit and develop into clones: 

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1. Though normalization, where a new mutation compensates for the original SBDS mutations. And 

2. Through transformation, where instead of addressing the original SBDS defect, the cells bypass quality control and tumor suppressor mechanisms and gain the potential to divide out of control. This is a maladaptive response and increases the risk of leukemia.

 

Let’s look at the difference between the two through an analogy. Imagine a stacking toy with colorful rings of different sizes to be stacked on a base, and the factory and machines that make them. The toy represents our blood with various blood cells. The factory represents the bone marrow, with the blood forming stem cells being the machines. 

• Scenario A, a healthy factory: To make the right amount of this toy for all the kids who want them, a healthy factory has to make the right amount and the right shape of all the rings. Let’s say 6 perfect sets per hour.

• Scenario B, representing SDS. The factory has a problem making enough toys, because the rings get stuck in the molds or spill over and several machines are out of service. It cannot meet the demand. The factory has two ways to increase production. 

• Scenario C. It can address the problem directly, by fixing some machines or by adding a non-stick coating to the mold. These strategies will increase the output, while still generating perfect sets of toys. The quality and quantity of toys will catch up to the healthy factory, but it won’t over produce the toys or sacrifice quality. This is a compensatory mechanism and represents normalization.

• Scenario D. It can completely ignore the quality issues and just increase the throughput. The rings still get stuck in the molds, but the factory just powers through. Output is increased, but without quality control, it's all junk. The factory is out of control. This is a maladaptive mechanism and represents transformation.

 

In SDS, both coping mechanisms have been observed. Several mutant clones are commonly observed in the bone marrow of SDS patients during their bone marrow surveillance over time. 

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• i(7q) - which provides an extra copy of a region of chromosome 7 that contains the leaky SBDS gene -  is a normalizing mutation. It increases the gene dose of SBDS. It’s like fixing the machines in the toy factory.

• del(20q) - which is a deletion of a section of chromosome 20, contains among many others a gene that is involved in ribosome assembly. New research indicates that mutations or deletions in this gene reduce the amount or function of EIF6, making it easier for SBDS to do its job in helping assemble the ribosome. It counteracts the SBDS defect, and is therefore compensatory / normalizing. It’s like adding non-stick coating to the machines.

• p53 loss, on the other hand, does not address the SBDS defect directly. Instead, it puts the stem cells on a path to acquire even more mutations and to divide uncontrollably without quality control. Like getting rid of quality control in the toy factory and ramping up production to the extreme, producing a huge amount of junk.
  
  It is not quite as simple as this, though. Up until now, it was not clear what role TP53 plays in SDS, except that it is often found in SDS patients (regardless whether they develop AML). New research indicates that one single  TP53 mutation by itself does not predict imminent leukemia risk. However, if the second copy of TP53 is lost as well, this complete TP53 inactivation indicates a strong increase in leukemia risk. 

 

Why is this important? 

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Because early detection of dangerous changes in the stem cells gives patients the best chance at survival. 

With this new understanding of which clones are good or bad, clinicians will be able to look for them during SDS patients’ regular surveillance. Current surveillance strategies rely on regular monitoring of blood counts, bone marrow morphology, and cytogenetics, but are not very sensitive for the detection of early signs of transformation. The addition of next-generation sequencing - a tool that can detect the mutations we just discussed and more - will enable the identification of clones that have an increased transformation risk sooner and thereby allow early intervention when the treatment options have the best outcomes -- such as preemptive bone marrow transplant...or gene therapy.

 

And finally, this research may also lead to the development of new biomarkers and clinically relevant endpoints for drug and therapy development.

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One Million Steps Closer to #CureSDS