Molecular and Genetic Mechanisms in Bone Marrow Failure Syndromes and Myeloid Neoplasia

Cleveland Clinic hematologist Jaroslaw Maciejewski, MD, PhD’s groundbreaking research efforts over two decades continue to decode the complex molecular and genetic mechanisms of bone marrow failure syndromes (BMFS) and myeloid neoplasia (MN). He and colleagues from Cleveland Clinic Cancer Center presented data from several ongoing studies at the 2020 annual meeting of the American Society of Hematology (ASH). Dr. Maciejewski, Chair of Cleveland Clinic’s Department of Translational Hematology and Oncology Research, shares his thoughts on two significant studies below.

Applying lessons learned in aplastic anemia

The first of these key studies found that the progression of aplastic anemia to MN is characterized by certain leukemogenic mutations or mutations in human leukocyte antigen (HLA), enabling clonal escape from immune surveillance.

“Aplastic anemia has been a very instructive disease that has led to tremendous progress in medicine including introduction of bone marrow transplantation, the concept of hematopoietic stem cells and much more,” says Dr. Maciejewski. “While there is growing success in treating aplastic anemia, one of the fearful complications of disease is the progression to leukemia and/or myelodysplastic syndrome (MDS).”

Researchers analyzed the progression from aplastic anemia to MDS to better understand the landscape of disease. The study examined 350 patients with aplastic anemia and paroxysmal nocturnal hemoglobinuria. Eleven percent (N = 38) developed a secondary MN. MDS was diagnosed in 77% of the patients, followed by acute myeloid leukemia in 21% of the patients. Pathogenic and likely pathogenic germline genetic variants included NF1, CBLC, SBDS and SAMD9L, and they were overall more frequently detected in del(7q) patients (76%). Chromosome 7 alterations were present in 47% of the patients (-7 in 35%; del(7q) in 12%), while complex karyotype involving chromosome 7 was found in 25% of the patients.

The analysis of myeloid and HLA panels revealed that, at the time of evolution, 34 of 38 patients had at least one of 148 somatic mutations detected, with an average of four somatic hits discovered per patient. Taken together, these findings demonstrate that the progression of aplastic anemia to MN is characterized by certain leukemogenic mutations or mutations in HLA, enabling clonal escape from immune surveillance.

Hereditary factors associated with predisposition to BMFS and MN

In the second study, investigators aimed to define the contribution of pathogenic germline genetic variants to the development of BMFS and MN in adults. While genetic alterations are well established as causes of leukemia and aplastic anemia in children, the role of hereditary factors in the development of these disorders in adults is less established.

The investigators sequenced a large panel of 150 genes associated with predisposition to leukemia and BMFS and established the frequencies of pathogenic alleles in 350 adults with BMFS and 2,827 adults with MN. They hypothesized that approximately 10% of patients, otherwise believed not to have hereditary disease, would have some genetic predisposition factors.

The team discovered that 10% of patients in the BMFS cohort had pathogenic and likely pathogenic germline variants (Tier-1), and 44% had suspicious germline variants of unproven clinical significance (Tier-2). Seven percent (N = 27) of patients were compound heterozygous carriers. Tier-1 variants included pathogenic mutations with known disease association, highly recurrent missense mutations found at a low frequency in the general population and frameshift/nonsense mutations.

“The results for myeloid neoplasia were surprising because they revealed that a significant proportion of adult patients also harbors inherited genetic predisposition factors,” notes Dr. Maciejewski.

“The classification of genetic alterations is evolving as we gain experience in assigning to them clinical significance,” he adds. “Tier-1 is highly likely related to the pathogenesis, or almost certainly contributing to the disease, while our understanding of Tier-2 needs to improve.”

Taken together, the two studies build upon a body of work dedicated to understanding the root causes, prognostic factors and optimal management of BMFS and MN.

Image: Confocal image showing the accumulation of myeloid hematopoietic cells throughout the mesenteric adipose tissue. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health. Licensed. No changes were made.