Telomere Diseases and Other Constitutional and Acquired Genetic Disorders of Hematopoiesis

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In the clinic, we continue to accrue patients to our current protocol of low doses of danazol, which includes ancillary testing by flow-FISH for telomere length, and both extended observation and wash-out periods (new patients were difficult to recruit during the pandemic). In collaborative efforts, another androgen, decadurabolin decanoate, was successful in in improving blood counts and effecting telomere elongation, which allows reliable discrimination of immune aplastic anemia from a variety of constitutional syndromes including Fanconi anemia, telomere biology disorders, RUNX1 deficiency, and Diamond-Blackfan anemia. Standard hematologic tests are sufficient, but telomere length is crucial to predictive accuracy. Our artificial intelligence tool is now publicly available at an NHLBI-hosted website. We are extending our machine learning approaches in a collaboration with a consortium of academic pediatric centers to improve diagnosis of individual constitutional syndromes, and in acquired aplastic anemia to distinguish low risk MDS from aplastic anemia and to predict clonal evolution in aplastic anemia. We have examined clonal hematopoiesis in recurrently mutated myeloid malignancy genes in patients with telomere disease and other syndromes. With a single exception, the presence of clonal hematopoiesis does not correlate with either clinical manifestations, outcomes, or survival, perhaps due to the time required for clones to expand in vivo. Second mutations in POT1 (which associate with germline TINF2 mutations) and in the promoter region of TERT appear to rescue the telomere deficient phenotype. However, clones mutated in U2AF1, an important spliceasome gene, appear as drivers of malignancy and strongly associate with a poor prognosis. Our clinic, in coordination with colleagues in NIAMS, is now a major referral center for VEXAS. In addition to detailed clinical characterization, we are now accruing to an interventional protocol for hematopoietic stem cell transplantation in VEXAS; engraftment in the first few patients has been unproblematic and the mutated clones have been eradicated with our conditioning regimens; complications of GVHD in this older population have been as anticipated and manageable. Clonal hematopoiesis is a feature of VEXAS, and also of other sydromes of pathologic inflammation. Secondary hematopoietic clones are frequent in VEXAS patients, particularly involving DNMT3A, a gene also frequent in clonal hematopoiesis of indeterminate prognosis (CHIP), and smaller clones involving TET2. Clonal expansion of the same pattern is also more frequent in general in autoinflammatory diseases, when adjusted for age, in young patients with Kawasaki arteritis to older patients with vasculitic syndromes. We have used single cell DNA sequencing with error correction to demonstrate variable clonal architectures in VEXAS cases: clones usually arise from the underlying UBA1 mutated stem cell, or in a branched pattern in parallel. Single cell RNA sequencing has been successfully applied to VEXAS bone marrow samples. Major results have been evidence of early myeloid lineage bias, deficient lymphoid maturation, and most prominently broad activation of inflammatory signaling in hematopoietic stem cells, involving interferon-gamma and -alpha and tumor necrosis factor pathways. Surprising have been findings of unexpected T cell clonality, not evident clinically despite B cell clonal manifestations like MGUS and multiple myeloma in patients, and upregulation of specific misfolded protein degradation pathways in hematopoietic cells.