Delighted to have our preprint led by @lvchosen1.bsky.social
up: Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells
biorxiv.org/content/10.1...

🧵 below ...

Grateful to have our research illustrated so beautifully by @atjcagan.bsky.social ! 🙏
Check out our work below, in which we describe inherited genetic resilience that protects some individuals from blood cancers 👇
www.biorxiv.org/content/10.1...

Congrats @hemagene.bsky.social and Jorge, awesome work!!

Out today in @science.org!
What if you could chart cells' regulatory programs at unprecedented resolution?
In my work with Jorge Martin-Rufino from the @bloodgenes.bsky.social lab, we dissect the genome’s control circuits and find where key genetic variation hides
bit.ly/3YhBMoO

So proud of this incredible work from @g-agarwal.bsky.social from our group with help from many fantastic folks in our lab and inspiring collaborators, including @kharaslab.bsky.social, Alex Bick, @yashpershad.bsky.social, and many others! Please check out Gaurav's awesome 🧵👇👇

I am hugely grateful for Vijay’s amazing mentorship and support, and the freedom he has given to pursue my scientific interests. I am incredibly optimistic in our vision to leverage human genetic resilience towards improved therapies for patients with blood disorders. Stay tuned! (end).

And to inspiring friends and colleagues in Sankaran Lab @mantoszewski.bsky.social, Uma Arora, @lvchosen1.bsky.social, Andrew Lee, Chun-Jie Guo, @lrbzldz.bsky.social, Laila Norford, @alneehus.bsky.social, Lucrezia della Volpe, Lara Wahlster and so many others, from whom I have learnt so much. (16/n)

None of this work would have been possible without the amazing support of brilliant collaborators @kharaslab.bsky.social, Alex Bick, @yashpershad.bsky.social, Ruslan Soldatov, Kathy McGraw, James Allan, Omar Abdel-Wahab, and others, who have brought so much expertise into this project. (15/n)

This work is the culmination of a Research Fellowship in the lab of @bloodgenes.bsky.social , who I first met in 2017 during a Harvard Stem Cell Institute internship. As fate would have it, I would return to work with Vijay 6 years later, with the generous support of a Kennedy Scholarship. (14/n)

Excitingly, our work provides human genetic evidence supporting inhibition of MSI2 (or its downstream targets) as rational approaches to enable blood cancer prevention. More broadly, we hope this will inspire further efforts to decode and leverage natural cancer resilience. (13/n)

Our findings uncover a germline mechanism directly protecting HSCs from blood cancers, by altering a post-transcriptional RNA network through reduced MSI2 levels, which attenuates the fitness advantage of CH. (12/n)

Moreover, we show in experimental models that reducing MSI2 levels protects human HSCs from phenotypic expansion in ASXL1-mutant CH, whilst MSI2 overexpression cooperates with Asxl1-/- in mouse models to induce myelodysplastic syndrome. (11/n)

Can rs17834140 protect from CH? In collaboration with @AlexBickMDPhD @yash_pershad, we show in a longitudinal cohort that rs17834140-T is associated with slower CH expansion rates, and predicts transience of large CH clones, implicating MSI2 levels as a modifier of HSC fitness. (10/n)

… thereby uncovering a network of MSI2-regulated mRNAs that are highly translated in human HSCs, and downregulated with inherited CH resilience. Strikingly, these mRNAs are reciprocally upregulated in TET2-CH, and enriched expression predicts poor prognosis in AML. (9/n)

So how does reduced MSI2 protect HSCs from blood cancers? In collaboration with @KharasLab, we mapped direct mRNA binding targets of MSI2 in human HSCs. Remarkably, the majority of MSI2-bound mRNAs were downregulated in CH-resilient HSCs with reduced MSI2 levels… (8/n)

MSI2 is an RNA-binding protein that regulates stem cells – but can downtuning its levels alter HSCs functionally? Yes! Genetic variation-driven loss of the MSI2 enhancer partially phenocopies complete MSI2-KO, reducing HSC maintenance and multilineage engraftment in xenografts. (7/n)

Through variant-to-function mapping, we show that rs17834140-T protects from CH through loss-of-function at an MSI2 enhancer. We model variant effect through CRISPR microdeletions, showing natural germline variation can protect from CH through reducing MSI2 levels in human HSCs. (6/n)

We dug deeper, uncovering rs17834140 as the likely causal variant at this locus – located in a regulatory element active selectively in HSCs – the cell type of origin in CH! We set out to mechanistically understand how rs17834140 modulates HSCs to confer blood cancer resilience. (5/n)

To identify protective effects, we conducted a GWAS meta-analysis of CH across population biobanks. We identified germline variation at the 17q22 locus associated with robust resilience to CH [OR=0.84] and myeloid malignancies [OR=0.80] in the population. (4/n)

Blood cancers are preceded by somatic mutations that drive expansion of hematopoietic stem cells (HSCs) – termed “clonal hematopoiesis” (CH). But CH also occurs ubiquitously in adults – so why do some progress to blood cancers, and others remain protected? (3/n)

Genetic variation protects some individuals from disease. Understanding natural resilience has enabled therapeutic development – e.g., BCL11A suppression for sickle cell disease and PCSK9 inhibition to reduce cardiovascular risk. Are there such opportunities for blood cancers? (2/n)

What protects individuals from developing blood cancers?

Thrilled to share my work in @bloodgenes.bsky.social lab, describing inherited resilience protecting blood stem cells from clonal hematopoiesis by modifying RNA regulation. 🧵👇 (1/n)
www.biorxiv.org/content/10.1...