AKIKO SHIMAMURA (BOSTON)
GERMLINE PREDISPOSITION TO MDS AND BONE MARROW FAILURE
Diagnosis of germline predisposition to MDS and bone marrow failure (BMF) has been
transformed by the availability of broad genetic testing. 1 Multiple studies demonstrate that
sole reliance on clinical phenotyping may miss cryptic presentations or result in misdiagnosis
from overlapping or atypical manifestations. Since some genes may be mutated either in the
germline or somatically, this distinction is essential to inform clinical management. 2
Prognosis after clonal progression to myeloid malignancy is abysmal for many of these genetic
disorders, but surveillance modalities for risk stratification are currently limited. 3 To
investigate the mechanisms mediating progression to MDS from BMF, we studied the
inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure
disorder with a high risk of myeloid malignancy. 4 We sequenced paired marrow and
fibroblast samples with whole exome sequencing to identify recurrently mutated genes. This
informed the design of a custom targeted genetic panel to analyze samples collected
longitudinally from 110 patients with SDS. Multiple independent somatic hematopoietic
clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53.
The fitness constraint exerted by germline SBDS deficiency drives selection of somatic clones
via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates
a compensatory pathway with limited leukemic potential by rescuing the underlying SDS
ribosome defect to enhance clone fitness while leaving checkpoint pathways intact. TP53
mutations define a maladaptive pathway with enhanced leukemic potential by inactivating
tumor suppressor checkpoints without correcting the ribosome defect. Subsequent
development of leukemia was associated with acquisition of biallelic TP53 alterations. These
results mechanistically link BMF-associated leukemia predisposition to germline genetic
constraints on cellular fitness, and provide a rational framework for clinical surveillance
strategies.
1. Kennedy AL and Shimamura A. Genetic predisposition to MDS: clinical features and clonal
evolution. Blood. 2019;133:1071-1085.
2. Godley LA and Shimamura A. Genetic predisposition to hematologic malignancies:
Management and surveillance. Blood. 2017;130:424-432.
3. Myers KC*, Furutani E*, Weller E, Siegele B, Galvin A, Arsenault V, Alter BP, Boulad F, Bueso-
Ramos C, Burroughs L, Castillo P, Connelly J, Davies SM, DiNardo CD, Hanif I, Ho RH, Karras N,
Manalang M, McReynolds LJ, Nakano TA, Nalepa G, Norkin M, Oberley MJ, Orgel E, Pastore YD,
Rosenthal J, Walkovich K, Larson J, Malsch M, Elghetany MT, Fleming MD and Shimamura A. Clinical
features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic
syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol.
2020;7:e238-e246.
4. Warren AJ. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome.
Adv Biol Regul. 2018;67:109-127.
5. Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, Muscato GM, Klein RH,
Ballotti K, Liu S, Harris CE, Galvin A, Malsch M, Dale D, Gansner JM, Nakano TA, Bertuch A, Vlachos A,
Lipton JM, Castillo P, Connelly J, Churpek J, Edward, JR, Hijiya N, Ho, RH, Hofmann I, Huang JN, Keel S,
Lamble A, Lau BW, Norkin M, Stieglitz E, Stock W, Walkovich K, Beottcher S, Brendel C, Fleming MD,
Davies SD, Weller EA, Bahl C, Carter SL, Shimamura A*, Lindsley RC*. BioRxiv 2020;
doi: https://doi.org/10.1101/2020.06.04.134692
*equal contribution
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES