Our lab seeks to understand the fundamental mechanisms that regulate hematopoietic stem cell (HSC) function and progression to hematological malignancies. One of our important themes is developing innovative primary human cell models, by genetic modification of primary HSCs or iPSC reprogramming and re-derivation of HSCs from iPSCs. We emphasize the discovery of novel genetic drivers of HSC function and malignancy to develop new therapeutic options, including:

 

 

See our publications here.

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Nuclear lamins in HSC function and nuclear morphology

Aberrant nuclear morphology is a hallmark of cancers. We seek to identify the fundamental mechanisms that regulate nuclear morphology and malignant progression. We recently identified lamin B1 as the key 5q gene recurrently deleted in MDS and AML. We discover that lamin B1 loss alters HSC function and genome stability, and induces aberrant nuclear morphology (Pelger-Huet nuclear anomaly) by regulating genome organization (Reilly et al. 2022).

 

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Aberrant splicing due to SF3B1 spliceosome mutations

Recurrent mutations in the splicing factor SF3B1 drive clonal expansion of HSCs, ineffective erythropoiesis, and formation of ring sideroblasts. We seek to develop new models and identify mis-spliced driver genes. We have developed an iPSC model of SF3B1-mutant MDS and identify mis-splicing of TMEM14C and ABCB7 as the cause of ring sideroblast formation (Clough et al. 2021).

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Tracking clonal evolution using iPSC reprogramming

HSCs evolve during postnatal life by accumulating somatic mutations. We have shown that iPSC reprogramming of MDS/AML cells can capture premalignant subclones informing the history of clonal evolution (Hsu et al. 2019). We have generated a large panel of iPSCs corresponding to different stages of clonal evolution are uncovering genomic and transcriptional changes underlying progression.

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We are incredibly grateful to these funders who support our research!