Citations 2
Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS
Li, Peng , Fnu, Alnoor, Xie, Wei , Williams, Margaret S., Feusier, Julie Feusier, Zhao, Xiangrong, Zheng, Gang , Zieski, Arthur, Tantravahi, Srinivas K. , Tashi, Tsewang , Patel, Jay , Miles, Rodney R., Jacobsen, Jeffrey, Sborov, Douglas W. , Szankasi, Philippe , Rindler, Paul M., Close, Devin , Ohgami, Robert S. , Li, Peng , Alnoor, Fnu , Williams, Margaret C. , Feusier, Julie , Ding, Yi , Zhao, Chen , Zieske, Arthur W., Zu, Youli , Raess, Philipp W. , Osman, Afaf E.G. , Patel, Ami B. , Matynia, Anna P., Menon, Madhu P , Jacobsen, Jeffrey, George, Tracy I.
No container title available | May 23, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract VEXAS (vacuoles, E1-ubiquitin-like modifier activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described autoinflammatory disorder caused by acquired UBA1 mutations in hematopoietic precursor cells. The prevalence, clinical significance, and genomic landscape of UBA1variants in patients with hematologic malignancies (HM) remains unexplored. We analyzed the genomic profiles of 86 patients carrying 17 different UBA1variants amongst an unbiased cohort of 8,976 HM patients. Specific genetic and clinical features seen more frequently in patients with UBA1 pathogenic variants (PV) versus those with variants of uncertain significance (VUS) included: marked male predominance (98% versus 80%, P=0.002), macrocytic anemia (MCV 105 ± 1.4 fl versus 96 ± 1.4 fl, p=0.01), frequent dominant clones without concurrent somatic variants (53% versus 15%, p=0.004), and association with molecularly distinct low-risk myelodysplastic syndrome (MDS; 13%) with superior overall survival (OS). Interestingly, while the genetic profiles of UBA1 PV patients resemble patients with clonal cytopenia of unknown significance (CCUS), rapid UBA1 clonal expansion predispose patients to convert to low-grade MDS with a notably hastened progression compared to UBA1 wild-type CCUS. This “clone surge to clinical stability” (CS) is a mechanism that emphasizes the unique pathobiology of UBA1mutations in VEXAS and supports it as a distinct entity.
Genetics and Pathologic Landscape of Lineage Switch of Acute Leukemia during Therapy: A Multi-institutional Study
Hu, Shimin , Zhou, Ting , Khanlari, Mahsa , Shi, Min , Cui, Wei , Peker, Deniz , Chen, Weina , Wang, Endi , Gao, Juehua , Shen, Qi , King, Rebecca L. , Obiorah, Ifeyinwa E. , Courville, Elizabeth L. , Nomura, Eric, Cherian, Sindhu, Xu, Mina L. , Wang, Wei , Wang, Sa A. , Khoury, Joseph D. , Shi, Min , Hu, Shimin , Curry, Choladda V. , Xie, Wei , Ji, Yuan , Wang, Xiaoqiong , Zhao, Chen , Burack, Richard , Takahashi, Koichi , Medeiros, L. Jeffrey
No container title available | October 16, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The dismal outcome of acute leukemia undergoing immunophenotype-switch, compounded by the increased incidence in the era of immunotherapy, highlights the need for in-depth systemic studies. We investigated the clinicopathological, cytogenetic, and molecular features of 33 patients experiencing switch between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The median duration from the primary diagnosis to lineage switch was 7.8 months, with the subsequent median survival being < 3 months. The majority experienced a transition from B-ALL to AML. The AML cases demonstrated a spectrum of differentiation, ranging from minimal to erythroid, with monocytic being the most common. Cytogenetic analysis revealed 11q23/KMT2A fusions as the most recurrent abnormalities (n = 18); also observed were complex karyotype, 7/7q-, 9p-/CDKN2A deletion, t(5;14)/TCLX3::BCL11b, t(8;9)/PCM1::JAK2, t(9;22)/BCR::ABL1, and t(12;19)/TCF3::ZNF384. Remarkably, in 60% of patients lacking KMT2A fusions, a chronic myeloid neoplasm was observed preceding the first leukemia. In contrast, no prior hematological malignancies were observed in KMT2A cases. Deep mutational profiling reinforced the inherent clonal relationship between the initial and subsequent leukemias, evident from the overlapping mutational signatures. The presence of distinct additional mutations across the two phases supports the long-standing theory of lineage switch emerging via divergent evolution of a multipotential progenitor.