Diagnosis of inherited marrow failure syndromes. Substantial advances have been recently made in identifying genes which are mutated in inherited marrow failure syndromes. However, our experience in the clinic is that many of the patients with these syndromes cannot be accurately classified as known syndromes. The prevalence of the unclassifiable syndromes, their clinical characteristics and the relationship to genes mutated in already categorized syndromes have never been studied. We analyzed data from the Canadian Inherited Marrow Failure Registry to answer these questions and found that the unclassifiable syndromes constitute a major portion of the group of inherited marrow failure syndromes (about a quarter), and present major diagnostic and therapeutic dilemmas. We have also shown that patients with a previously unclassifiable marrow failure syndrome with defect in body balance and blood counts may have a disease called dyskeratosis congenita.
Preleukemia/leukemia. Leukemia and pre-leukemia (myelodysplastic syndromes, MDS) are common in marrow failure syndromes and has extremely poor outcome, but the mechanism of leukemogenesis is unknown. We used Shwachman-Diamond syndrome (SDS) marrow cells as a model to study gene expression pattern which might be associated or possibly mechanistically related to leukemia. We have found that SDS marrow cells exhibit abnormal expression pattern of leukemia-related genes, which might results in continuous stimulation favoring evolution or progression of malignant cells. In addition, as part of a collaborative study with the Severe Congenital Neutropenia International Registry Board, the group published the results of correlation analysis between ELA2 mutation in severe congenital neutropenia and the development of pre-leukemia/leukemia. The results showed that both patients groups are at risk of developing this complication, and thus should be followed closely for leukemic transformation.
Shwachman-Diamond syndrome (SDS). We discovered that marrow stem cells are reduced in number, grow poorly, die prematurely and are hypersensitive to the cell death protein, Fas. We also showed that SDS microenvironment is unable to support growth of normal marrow cells and is characterized by increased angiogenesis.
Kostmann neutropenia. Certain patients with this pre-leukemic syndrome do not respond to treatment with G-CSF. We have found that a novel mutation in the extracellular part of the G-CSF receptor molecule can lead to defective activation of the G-CSF pathway. Using cellular methods we showed that the abnormality can be corrected by prednisone, and a successful regimen using a combination of G-CSF and prednisone was developed. Interestingly, we have found that such a mutation might offset of the pro-proliferative effect of pre-leukemic mutations in the intracellular domain of the receptor.
Severe aplastic anemia. We reviewed our institutional experience, and showed that there has been a striking improvement in survival for paediatric patients treated with multi-agent immunosuppression in the last decade. However, transplantation results have also improved and this remains the first-line therapy for children with severe acquired aplastic anemia who do not have a matched relative donor for bone marrow transplantation. In addition, the risk factors for development of severe aplastic anemia are largely unknown. As a collaborative study with the USA National Institute of Health in Bethesda, the group showed that heterozygosity for SBDS mutations predisposes to severe aplastic anemia by accelerating telomere shortening via a telomerase-independent mechanism.
Bone marrow transplantation. The accelerated apoptosis in inherited marrow failure syndromes inspired us to develop innovative, reduced toxicity bone marrow transplantation regimens without radiation with promising preliminary results.
Neutrophil engraftment post BMT. Through a collaborative work, a mouse model to study neutrophil engraftment after bone marrow transplantation was generated in the laboratory of Dr. Michael Glogauer from the University of Toronto.
Canadian Inherited Marrow Failure Registry (CIMFR). In 2001 we established the CIMFR to register all patients with IMFSs in Canada and to bank biological samples for fundamental and translational research. This endeavour turned into a big success and thus far, 15 of the 17 Canadian academic Haematology/Oncology centres are participating and approximately 250 patients have been registered.