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Publications of the Week

Reprogramming Identifies Functionally Distinct Stages of Clonal Evolution in Myelodysplastic Syndromes

By July 24, 2019No Comments

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This week we profile a recent publication in Blood from the laboratory of Dr. Sergei Doulatov (pictured, left) at UW.

Can you provide a brief overview of your lab’s current research focus?

The Doulatov lab seeks to understand how genetic alterations in normal hematopoietic stem cells (HSCs) drive the development of myeloid neoplasms, including myelodysplastic syndromes (MDS) and acute leukemias. We are interested in understanding the trajectories of premalignant clonal evolution and their impact on HSC differentiation and self-renewal. We utilize primary human cells and induced pluripotent stem cells (iPSCs) to create models of hematological disorders. By combining reprogramming with genome sequencing and gene editing, we aim to reconstruct how pathogenic mutations cooperate to drive malignant transformation and develop new therapeutic interventions.

We are also interested in the biology of normal human hematopoiesis and erythropoiesis, with the focus on autophagy and mitophagy, key metabolic pathways for recycling damaged cellular components implicated in stem cell function and aging. Current goals involve understanding the role of autophagy in different hematopoietic cell types, defining cell-type specific molecular regulators of autophagy and mitophagy, and development of autophagy therapeutics.

What is the significance of the findings in this publication?

Despite advances in our genomic understanding of cancer evolution, developmental origins of MDS and AML remain poorly understood. One question of intense interest in the field is how acquisition of somatic mutations contributes to progression from premalignant HSCs to MDS and malignancy. In this paper, we show that episomal reprogramming of MDS and AML patient samples to iPSCs captures these premalignant intermediates revealing the molecular stages by which an individual cancer has evolved. By differentiating these distinct iPSCs to hematopoietic progenitors, we can study how acquisition of mutations affects the differentiation into various blood lineages. This reprogramming approach thus uniquely enables both molecular and functional study of cancer evolution.

What are the next steps for this research?

In this paper, we studied a relatively small number of patients. The next steps would be to study a larger cohort of MDS and AML patients and begin identifying patterns and rules governing cancer evolution at the clonal or single cell level. At the same time, we would like to combine reprogramming with other new technologies including single cell genomics and RNA sequencing to get an even deeper look into some of these processes. Another direction is to look deeper at different subtypes of MDS or leukemia to study how specific oncogenic drivers cooperate to promote disease.

This work was funded by:

We received support from my K99/R00 transition to independence award, New Innovator Award, EvansMDS Foundation, as well as local support from Cancer Consortium/Safeway and ISCRM/Tietze family.

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