Inherited Bone Marrow Failure Syndromes as Experiments of Nature for Blood Diseases

Emerging evidence regarding the genetic pathways involved in Scwachman-Diamond syndrome and Severe Congenital Neutropenia

By Seth J. Corey, MD, MPH

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Cancer is a disease due to the acquisition of somatic mutations; it is a disease of aging.  So, why do children develop cancer? That’s the question my lab has been studying by focusing on acute myeloid leukemia (AML). Less common than acute lymphoblastic leukemia (ALL) among the pediatric population, AML has a cure rate of only 50-60%. We need greater understanding of how AML arises to design more effective therapies.

We appreciate that cancer may have roots in our germline genetic constitution. This is certainly the case with the inherited bone marrow failure syndromes (IBMFS) that I study in the laboratory and manage in the clinic. Types of IBMFS include: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome (SDS), Severe Congenital Neutropenia (SCN, previously known as Kostmann syndrome), GATA2 deficiency and congenital amegakaryocytic thrombocytopenia. Phenotypically, there is some variability in the period of latency to complete bone marrow failure, involvement of other organ systems and risk of transforming into AML or a solid tumor.

Experiments of nature

These disorders are “experiments of nature.” The genes for most of the IBMFS have been identified, and for each disorder, the genes belong to a particular pathway. Fanconi anemia is due to mutation in one of about two dozen genes involved in DNA double strand break repair. Diamond-Blackfan anemia is due to mutation in one of the many genes encoding a component of the ribosome. Dyskeratosis congenita results from a mutation in one of the genes involved in protecting the telomere. Less clear is the pathway involved in the inherited neutropenias (SCN and SDS) that we study. Evidence is emerging that they may result from defects in protein production, quality and trafficking.1

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One obstacle to understanding these disorders and their complications is the rarity of each condition. The both have an incidence of approximately one in 100,000. We have turned to studying SDS in the zebrafish.2 There are advantages to studying zebrafish over mice: organogenesis is completed within 96 hours, their development is transparent, they lay hundreds of eggs at a time permitting statistical anaylsis, and they are inexpensive to maintain. Fortuitously, the similarity between human and zebrafish SDS protein is almost 90%. Using CRISPR genome editing, Usua Oyarbide, PhD, created a zebrafish model of SDS in my lab. The fish display the same features as children with SDS: small stature, neutropenia and pancreatic atrophy. Tissue analysis showed defects that are more widespread. Gene expression analysis identified a cellular stress response involving p53, sometimes referred to as the guardian of the genome. More excitingly, Dr. Oyarbide has introduced one of the mutated genes for human SDS into the fish. This will permit us to identify the additional genetic changes required to produce AML, as children with SDS have a 1,000-fold increased risk of developing AML.

Predicting clonal competition and outgrowth

Those with SCN who develop AML acquire mutations in the receptor for granulocyte colony-stimulating factor (GCSF, known as filgrastim). The mutations occur spontaneously in some children, and the high, chronic doses of filgrastim permit clones to flourish and dominate. We have identified signaling events for GCSF Receptor and the mutant forms.3-6 We have identified differences in phosphorylated proteins at early time points (less than two hours) and gene expression changes at later time points (more than two hours). We have used deep sequencing of DNA to determine mutation rates due to intracellular stress responses associated with SCN. We are correlating these biochemical and genetic events with clonal bad behavior, and developing mathematical models to predict clonal competition and outgrowth.7 With this information and machine learning, our goal is to intervene in those patients at highest risk of AML before the leukemic clones are established.


  1. Oyarbide U, Corey SJ. SRP54 and a Need for a New Neutropenia Nosology. Blood. 2018;132(12):1220-22.
  2. Oyarbide U, Topczewski J, Corey SJ. Peering Through Zebrafish to Understand Inherited Bone Marrow Failure Syndromes. Haematologica. 2019;104(1):13-24.
  3. Corey SJ, Burkhardt AL, Bolen JB, Gaehlen RL, Tkatch LS, Tweardy DJ. Granulocyte Colony-Stimulating Factor Receptor Signaling Involves the Formation of a Three-Component Complex With Lyn and Syk Protein-Tyrosine Kinases. Proc Natl Acad Sci U S A. 1994; 91(11):4683-7.
  4. Corey SJ, Dombrosky-Ferlan PM, Zuo S, et al. Requirement of Src Kinase Lyn for Induction of DNA Synthesis by Granulocyte Colony-Stimulating Factor. J Biol Chem. 1998;273(6):3230-5.
  5. Mehta HM, Glaubach T, Long A, et al. Granulocyte Colony-Stimulating Factor Receptor T595I (T618I) Mutation Confers Ligand Independence and Enhanced Signaling. Leukemia. 2013;27(12):2407-10.
  6. Mehta HM, Futami M, Glaubach T, et al. Alternatively Spliced, Truncated GCSF Receptor Promotes Leukemogenic Properties and Sensitivity to JAK Inhibition. Leukemia. 2014; 28(5):1041-51.
  7. Wojdyla T, Metha H, Glaubach T, et al. Mutation, Drift and Selection in Single-Driver Hematologic Malignancy: Example of Secondary Myelodysplastic Syndrome Following Treatment of Inherited Neutropenia. PLoS Comput Biol. 2019;15(1):e1006664.