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Seeking (Relation)CHIP Advice

December 11, 2021

Swiping Right on Clonal Hematopoiesis at This Year’s Meeting

Natasha Szuber, MSc, MD

Dr. Natasha Szuber (@NatashaSzuber) is a hematologist-oncologist at Maisonneuve-Rosemont Hospital, University of Montreal in Quebec, Canada, specializing in myeloid disorders, particularly myeloproliferative neoplasms, and has further interests in clonal hematopoiesis and iron metabolism. She received her MSc at McGill University in Montreal, her MD at University of Montreal, and did her Advanced Hematology Myeloid Fellowship at Mayo Clinic in Rochester, Minnesota. Dr. Szuber remarked that she was “born, raised, and currently still residing in Montreal…It's a beautiful, vibrant city if you can look past the orange construction cones and innumerable potholes!” 

While Dr. Szuber is “relatively new” to the ASH family, she is looking forward to collaborating further in coming years and was just selected to participate in the ASH Clinical Research Training Institute this year. Fun fact: Dr. Szuber enjoyed a “past life as an aspiring rock n' roll star, recorded three albums, and toured with my band across Canada before finally surrendering to the call to med school.” 

 

Dear ASH News Daily: I consider myself a garden-variety hematologist. I have my virtues and shortcomings, do my utmost to stay up-to-date via the now ubiquitous Zoominars, and still enjoy the simple and tactile pleasure of leafing through the abstracts of my beloved piles of Blood journals. And while most of the time I know my ARCH (age-related clonal hematopoiesis) from my ICUS (idiopathic cytopenia of undetermined significance) from my CCUS (clonal cytopenia of undetermined significance) from my IBMFS (inherited bone marrow failure syndromes), this year I’m finding it challenging to keep up. You see, the once blithesome bachelor CHIP, a.k.a. clonal hematopoiesis of indeterminate potential (and similarly abbreviated precursor condition confrères), has been fraternizing with some very strange bedfellows. Just when I thought I had sorted the little black book of entangled acronyms, perusing this year’s abstracts on unexplained blood cytopenias and related entities became the hematologic equivalent of peeking through a dating log from ABC’s hit TV show, The Bachelorette (I mean, not that I’ve ever seen the show, but I’ve heard… from friends). The recently exposed, now not-so-secret liaisons between CHIP and essentially “fill-in-the-blank” (try multiple myeloma, Alzheimer’s disease, solid tumors, etc.) made me wonder, what hasn’t clonal hematopoiesis been linked to? Not to mention the bevvy of novel techniques, including single cell, murine models, and CRISPR/Cas9, being exploited to elucidate the underpinnings of these predisposition entities. So, at the heart of it, I guess I’m just a hematologist, standing before an ASH News Daily column, asking for help sorting through clonal hematopoiesis at this year’s meeting 
Sincerely, 
(Relation)CHIP on the rocks 

Dear “on the rocks”: These clinical conditions flirting with myelodysplasia are also pining for your affection, so consider us your conference cupid, here to provide tips and tactics to find your best matches for clonal hematopoiesis at the 63rd ASH Annual Meeting. 

We’re handing out our first rose to the Education Program session “Let the CHIP(s) Fall Where They May? Burdens and Benefits of Diagnosing Clonal Hematopoiesis” (with virtual and in-person live Q&A, on Sunday, December 12). Dr. Lukasz Gondek, who will be acting as both chair and panelist, recently summarized how the session would delve into “the etiology of somatic mutations in hematopoietic tissue [and] the mechanism of clonal expansion with aging and in the context of various germline hematopoietic stem cells defects underlying bone marrow failure.” He expressed he was most excited to “hear about the novel insights into the biology of clonal hematopoiesis as well as the most recent clinical recommendations for monitoring, surveillance, and management.” And if you’re wondering how this all fits into your practice, Dr. Gondek reassured us: “We will explain the role of molecular testing and the presence of clonal hematopoiesis in the work-up and diagnosis of myeloid malignancies and myeloid precursor states.” Taking a cue from this, Dr. Afaf Osman will be detailing practical diagnostic approaches to myeloid precursor states using a case-based approach while Dr. Moonjung Jung will be profiling IBMFS. We caught up with Dr. Jung as she outlined the distinct features of clonal hematopoiesis observed in IBMFS. “Firstly, the onset of clonal hematopoiesis tends to be much younger; secondly, the mutation spectrum can be quite different; lastly, clonal hematopoiesis is not always a bad sign … if a randomly occurring somatic mutation happened to be correcting underlying defects,” she said, citing the example of “EIF6 mutations in Shwachman-Diamond syndrome.” Regarding future directions, she elaborated, “While there is an explosive amount of new information about clonal hematopoiesis in IBMFS, clearly we need to understand disease mechanisms better and perform clinical trials step by step to apply our new knowledge to improve patient outcomes.” 

Looking to marry both the fundamental science and clinical ramifications of clonal hematopoiesis in poster format? Look no further than the “Clonal Hematopoiesis, Aging and Inflammation: Poster II session taking place on Sunday, December 12, at 6:00 p.m. ET. Among the highly compatible prospects, “Characteristics and Clinical Outcome of Patients with Clonal Cytopenias of Undetermined Significance: A Large Retrospective Multi-Center International Study” presented by Dr. Zhuoer Xie will detail somatic mutations and their prognostic associations in an extensive CCUS cohort. Exploring the nexus of clonal hematopoiesis and colorectal cancer, Dr. Yang Feng’s work “Dnmt3a Mutations in the Hematopoietic System Promote Colitis-Associated Colon Cancer: A Model of Clonal Hematopoiesis in Solid Tumors,” will reveal new insights into mechanisms of carcinogenesis and their interrelationships with both hematopoietic and immune systems.  

Meet the heartthrobs of the oral abstracts included in the session “Clonal Hematopoiesis, Aging and Inflammation: Mechanisms, Disease Associations and the Impact of Aging” scheduled for Monday, December 13, at 10:30 a.m. ET that will take us from “The Association between Clonal Hematopoiesis and Gout” to “Tracing the Evolution of Clonal Hematopoiesis to AML Using Longitudinal Pre-Diagnosis Blood Samples” presented by Drs. Mridul Agrawal and Caroline J. Watson, respectively. On a mechanistic level, having used the innovative method PACER (passenger-approximated clonal expansion rate) to infer expansion rates of premalignant clones, Dr. Jk Gopakumar will disclose how TCL1A activation may confer fitness advantage of driver genes in CHIP and hematologic cancers with therapeutic implications in “Clonal Hematopoiesis Is Driven by Aberrant Activation of TCL1A.” Furthermore, the Late-Breaking Abstracts Session taking place on Tuesday, December 14, at 9:00 a.m. ET will include “The Longitudinal Dynamics and Natural History of Clonal Hematopoiesis” by Dr. Margarete A. Fabre and her group, characterizing clonal dynamics throughout the human lifespan and providing pivotal insights into the associations between somatic mutations, aging, clonal selection, and malignant progression. 

CHIP will also be one of the main squeezes of the Plenary Scientific Session scheduled for Sunday, December 12, at 2:00 p.m. ET. “Clonal Hematopoiesis is Associated with Reduced Risk of Alzheimer’s Disease” presented by Dr. Hind Bouzid will explore the somewhat murkier-than-expected relationship between CHIP and Alzheimer’s disease with surprising conclusions and novel links involving the immune system and the aging brain. 

In the end, dear “on the rocks,” after the final rose has been dispensed, we humbly acknowledge that both relationships and clonal hematopoiesis will remain under the complex governance of natural selection and evolutionary cunning. While we have made great strides in uncovering the partners and adversaries of CHIP, ICUS, CCUS, and company, their dance cards are far from full, and we still have much to learn about their biology and clinical repercussions. The one sure thing, however, is that our love affair with these emerging predisposition entities has only just begun…  

Dr. Szuber indicated no relevant conflicts of interest. 

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