Advertisement


Irene Roberts, MD, on Leukemogenesis in Infants With Trisomy 21

2022 ASH Annual Meeting and Exposition

Advertisement

Irene Roberts, MD, of Oxford’s Weatherall Institute of Molecular Medicine, discusses children with Down syndrome, who have a more than 100-fold increased risk of developing acute myeloid leukemia before their fourth birthday compared to children without Down syndrome. Their risk of acute lymphoblastic leukemia is also increased by around 30-fold. Dr. Roberts details current knowledge about the biologic and molecular basis of this relationship between leukemia and Down syndrome, the role of trisomy 21 in leukemogenesis, and the clinical implications of these findings.



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Children with Down syndrome have an increased susceptibility to leukemia. This is an important topic and a relevant topic for hemato-oncologists, both because Down syndrome is a relatively common cause of morbidity and premature mortality worldwide, but also because it offers us scientific insights into the impact of Trisomy 21, and probably aneuploidy in general into the behavior of hemopoietic cells. Now, one of the interesting things is that both acute myeloid leukemias and acute lymphoblastic leukemias are increased in children with Down syndrome, and it's particularly young children that are affected by these leukemias. This increase in leukemia occurs actually at the expense of a reduction in solid tumors. Solid tumors occur at only half the expected incidence in individuals with Down syndrome, with the exception of germ cell tumors that is. Let's consider first myeloid leukemias of Down syndrome, which are a unique form of acute myeloid leukemia, and present usually in children under the age of four years. Myeloid leukemias in Down syndrome are typically erythro and megakaryoblastic, and they are initiated in utero. In many cases, they're preceded by an overt form of neonatal pre-leukemia called transient abnormal myelopoiesis or TAM. But this may be completely clinically silent. We know that both TAM and ML-DS are caused by somatic mutations in the Megacaryocyte Erythroid transcription factor, GATA-1. We now know that the frequency of these mutations is particularly high in neonates with Down Syndrome. However, in most cases, these mutations resolve completely over the first two to three months of life. In about 20% of cases, however, mutant GATA-1S containing cells persist and acquire additional mutations, and it's that scenario that gives lives to the condition, ML-DS. Usually when the mutations are loss of function mutations in cohesive genes. The risk of transformation to ML-DS is highest in those with an increased disease burden, and we know that this cannot be prevented by current therapies. Now, in contrast to ML-DS, acute lymphoblastic leukemia in Down Syndrome is not caused by mutations in GATA-1. Instead, there are a number of other distinctive features of ALL in Down syndrome. For example, it's always B-lineage, and T-lineage in infant leukemia is extremely rare in Down syndrome. The mutations which are known to cause leukemia in children with Down syndrome involve mutations of the CRLF2 receptor gene, often in combinations with activation mutations in the JAK2 gene, or for those that are JAK2 wild-type RARS mutations. From the clinical point of view, the importance of ALL in Down syndrome is that the outlook of treatment for children with Down syndrome is inferior to those who do not have Down syndrome. Now, one of the big questions in the field is why it is that Trisomy 21 is associated with such a high risk of leukemia, and current views about the mechanisms postulate that this is likely to involve a combination of altered gene dosage of epigenetic adaptations to mitigate the potentially adverse effects of increased gene expression by chromosome 21, and in the setting of childhood leukemia, in particular, the impact of Trisomy 21 on the microenvironment and the interaction of all of these factors with ontogeny-related gene expression programs.

Related Videos

Multiple Myeloma
Genomics/Genetics
Immunotherapy

Francesco Maura, MD, on Genomic Determinants of Resistance in Newly Diagnosed Multiple Myeloma Treated With Targeted Immunotherapy

Francesco Maura, MD, of the University of Miami, Sylvester Comprehensive Cancer Center, discusses his team’s findings in which they defined a comprehensive catalogue of genomic determinants of response to DKRd (carfilzomib, lenalidomide, dexamethasone) in newly diagnosed multiple myeloma. The researchers have identified a number of new genomic alterations that explain resistance to the agents currently used in combination regimens (Abstract 470).

 

Hematologic Malignancies
Immunotherapy

Joseph Schroers-Martin, MD, on Posttransplant Lymphoproliferative Disorders: Tumor Microenvironment Determinants of Immunotherapy Response

Joseph Schroers-Martin, MD, of Stanford University, discusses immunogenomic features reflecting divergent biology in posttransplant lymphoproliferative disorders (PTLD). These include evidence of mismatch repair defects in Epstein-Barr virus–positive PTLD, tumor microenvironment depletion, and MYC pathway enrichment in certain patients (Abstract 72).

Hematologic Malignancies
Genomics/Genetics

Smita Bhatia, MD, MPH: Some Clonal Mutations May Predict Therapy-Related Myeloid Neoplasms

Smita Bhatia, MD, MPH, of the Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, discusses study findings that showed key somatic mutations in the peripheral blood stem cell product increases the risk of developing therapy-related myeloid neoplasms (Abstract 119).

Lymphoma
Immunotherapy

Tycel J. Phillips, MD, on Mantle Cell Lymphoma: New Findings on Glofitamab Monotherapy

Tycel J. Phillips, MD, of the City of Hope National Medical Center, discusses data that showed fixed-duration glofitamab monotherapy induced high and durable complete response rates in patients with mantle cell lymphoma (MCL) who received obinutuzumab pretreatment. This is one of the largest data sets and longest follow-ups reported with a CD20/CD3 bispecific monoclonal antibody for patients with relapsed or refractory MCL (Abstract 74).

Leukemia
Issues in Oncology

Abdul Rahman Al Armashi, MD, on AML: Racial Disparities in Mortality Trends

Abdul Rahman Al Armashi, MD, of Seidman Cancer Center, Case Western University, University Hospitals Cleveland Medical Center, discusses a retrospective analysis, using a CDC database, in one of the largest subgroup-based racial population studies analyzing mortality trends in patients with acute myeloid leukemia (AML). Between 2000 and 2019, AML mortality was the highest in Whites and the lowest in American Indians or Alaska Natives. The highest rate of increase in mortality was seen in Asians or Pacific Islanders. Dr. Al Armashi talks about the many variables that might contribute to these inequalities (Abstract 600).

Advertisement

Advertisement




Advertisement