University of Wisconsin Hematology

Biology of cancer; CHIP, CCUS and VEXAS

  1. Siegel et al. Cancer statistics, 2015. CA 2015;65: 5
  2. Jamieson and Weissman. Stem-Cell Aging and Pathways to Precancer Evolution. NEJM 2023;389:1310
  3. Fröhling and Döhner. Chromosomal abnormalities in cancer. NEJM 2008;359:722
  4. Croce C. Oncogenes and cancer. NEJM 2008;358:502
  5. Uhlen et al. A pathology atlas of the human cancer transcriptome. Science 2017;357:eaan2507
  6. Dawson MA. The cancer epigenome: Concepts, challenges, and therapeutic opportunities. Science 2017;355:1147
  7. Huff et al. The paradox of response and survival in cancer therapeutics. Blood 2006;107:431(Cancer stem cells)
  8. Vogelstein et al. Cancer genome landscapes. Science 2013;339:1546
  9. Hahn and Weinberg. Rules for making human tumor cells. NEJM 2002;347:1593
  10. Kwok et al. DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies. Blood 2024;143:2123
  11. Hotchkiss et al. Mechanisms of disease: cell death. NEJM 2009;1570
  12. Palucka and Coussens. The basis of oncoimmunology. Cell 2016;164:1233
  13. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. NEJM 2016;375:1767
  14. Binnewies et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018;24:541
  15. Tomasetti and Vogelstein. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78(Oncogenic mutations happen in proportion to the number of dividing stem cells in a tissue; with editorial)
  16. Popovic et al. Ubiquitination in disease pathogenesis and treatment. Nat Med 2014;20:1242
  17. Esteller M. Epigenetics in cancer. NEJM 2008;358:1148
  18. Aparicio and Caldas. The implications of clonal genome evolution for cancer medicine. NEJM 2013;368:842
  19. Yue and Rao.TET family dioxygenases and the TET activator vitamin C in immune responses and cancer. Blood 2020;136:1394
  20. Roodman GD.  Mechanisms of bone metastasis.  NEJM 2004;350:1655
  21. Chiang and Massagué. Molecular basis of metastasis. NEJM 2008;359:2814
  22. Leong and Karsan. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006;107:2223
  23. Platanias L.  MAP kinase signalling pathways and hematologic malignancies.  Blood 2003;101:4667
  24. Chen et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 2016;535:148
  25. Murtaza et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013;497:108
  26. Andor et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med 2016;22:105
  27. Casey et al. The MYC oncogene is a global regulator of the immune response. Blood 2018;131:2007(“MYC may…prevent highly proliferative cells from eliciting an immune response. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions”)
  28. Xu et al. Cancer and platelet crosstalk: opportunities and challenges for aspirin and other antiplatelet agents. Blood 2018;131:1777
  29. Gordon-Alonso et al. Extracellular galectins as controllers of cytokines in hematological cancer. Blood 2018;132:484
  30. Reiter et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 2018;361:6406(A single biopsy provides adequate information about driver genes in metastatic disease)
  31. Helmink et al. The microbiome, cancer, and cancer therapy. Nat Med 2019;25:377
  32. Duncan et al. Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.  NEJM 2024;391:1287

CHIP & CCUS

  1. Malcovati and Cazzola. How I manage patients with unexplained cytopenia. Blood 2025;145:1610
  2. Fabre and Vassiliou. The lifelong natural history of clonal hematopoiesis and its links to myeloid neoplasia. Blood 2024;143:573
  3. Weeks and Ebert. Causes and consequences of clonal hematopoiesis. Blood 2023;142:2235
  4. Weeks et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid 2023 (Epub) (A risk score to predict likelihood of myeloid neoplasm in CH)
  5. Xie et al. Risk prediction for clonal cytopenia: multicenter real-world evidence. Blood 2024;144:2033 (3-parameter risk score including  presence of splicing mutation, plts < 100K and 2 or more mutations predict progression)
  6. Boettcher and Ebert. Clonal hematopoiesis of indeterminate potential. J Clin Oncol 2019;37:419
  7. Challen and Goodell. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 2020;136:1590
  8. Warren and Link. Clonal hematopoiesis and risk for hematologic malignancy. Blood 2020;136:1599
  9. Jaiswal S. Clonal hematopoiesis and nonhematologic disorders. Blood 2020;136:1606
  10. Shlush LI. Age-related clonal hematopoiesis. Blood 2018;131:496
  11. Jaiswal et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. NEJM 2014:371:2488(>10 fold increased risk of heme malignancy in pts with somatic mutations in peripheral blood cells)
  12. Xie et al.Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014;20:1472(“The blood cells of more than 2% of individuals [5–6% of people older than 70 years] contain mutations that may represent premalignant events)
  13. Rossi et al. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years. Blood 2021;138:2093 (Specific mutational patterns predict risk of evolution to myeloid neoplasia)
  14. Watson et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 2020;367:6485
  15. Genovese et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. NEJM 2014;371:2477(Results similar to above article)
  16. Steensma et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126:9
  17. Steensma D. Predicting therapy-related myeloid neoplasms – and preventing them? Lancet Oncol 2017;18:11(Overt malignancy develops at a rate of 0.5-1% per year in people with CHIP)
  18. Jaiswal et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. NEJM 2017;377:111(CHIP associated with 2x higher risk of CAD in humans and accelerated atherosclerosis in mouse model)
  19. Libby abd Ebert. CHIP (Clonal Hematopoiesis of Indeterminate Potential). Potent and Newly Recognized Contributor to Cardiovascular Risk. Circulation 2018;138:666
  20. Arends et al. Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke. Blood 2023;141:787
  21. Miller et al. Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood 2022;139:357
  22. Agrawal et al. TET2-mutant clonal hematopoiesis and risk of gout. Blood 2022;140:1094
  23. Zink et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 2017;130:742 (Evidence of clonal hematopoiesis found in less than 1% of those under 35 and over 50% in those over 85)
  24. Buscarlet et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 2017;130:753(TET2 mutations age-dependent, associated with mild neutropenia, showed some familial clustering)
  25. Malcovati et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 2017;129:3371(Presence of somatic mutation increased likelihood of developing a myeloid neoplasm by about 14-fold)
  26. van Zeventer et al. Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals. Blood 2020;135:1161
  27. Cooper and Young. Clonality in context: hematopoietic clones in their marrow environment. Blood 2017;130:2363
  28. Nagase et al. Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. J Exp Med 2018;215:1729(Mouse model of CHIP; see this discussion in NEJM)
  29. Meisel et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 2018;557:580
  30. Desai et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med 2018;24:1015(IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome gene mutations predict progression to AML; with editorial)
  31. Loh et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 2018;559:350(Identifies several genetic loci that substantially increase risk to develop CHIP)
  32. Hansen et al. Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality. Blood 2020;135:261(No evidence that there is a genetic predisposition to CHIP or that it increases mortality)
  33. Fabre et al. Concordance for clonal hematopoiesis is limited in elderly twins. Blood 2020;135:269
  34. Bick et al Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2020;586:763
  35. DeBoy et al. Familial Clonal Hematopoiesis in a Long Telomere Syndrome. NEJM 2023;388:2422
  36. Tsaknakis et al. Incidence and prognosis of clonal hematopoiesis in patients with chronic idiopathic neutropenia. Blood 2021;138:1249 (Prevalence <3%, 31-fold higher risk of transformation to myeloid neoplasm)
  37. Galli et al. Relationship between clone metrics and clinical outcome in clonal cytopenia. Blood 2021;138:965 (30% of patients with idiopathic cytopenia have CCUS)
  38. Vlasschaert et al. Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury. Nat Med 2024;30:810
  39. Pich et al. Tumor-Infiltrating Clonal Hematopoiesis. NEJM 2025;392:1594 (CH cells remodel tumor microenvironment, increase recurrence risk; with editorial)

VEXAS syndrome & related conditions

  1. Beck et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. NEJM 2021;383:2628 (“VEXAS” syndrome, X-linked condition – somatic hematopoietic stem cell mutations impair ubiquitination and protein degradation in phagocytes, activate autoimmune pathways; with editorial)
  2. Koster et al. VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management. Am J Hematol 2024;99:284 
  3. Sirenko et al. Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes. Blood 2024;144:1221 (Found in 1% of MDS patients, all male. 83% had inflammatory presentation)
  4. Arlet et al. Mutant UBA1 and Severe Adult-Onset Autoinflammatory Disease. NEJM 2021;384:2163(VEXAS syndrome in 2 women with acquired monosomy X)
  5. Grayson et al. VEXAS syndrome. Blood 2021;137:3591
  6. Bourbon et al. Therapeutic options in VEXAS syndrome: insights from a retrospective series. Blood 2021;137:3682
  7. Gurnari et al. Vacuolization of hematopoietic precursors: an enigma with multiple etiologies. Blood 2021;137:3685
  8. Ferrada et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis Blood 2022;140:1496
  9. De Langhe et al. TET2-Driver and NLRC4-Passenger Variants in Adult-Onset Autoinflammation. NEJM 2023;388:1626 (VEXAS-like syndrome with TET2-driven myeloid clone bearing an NLRC4 variant causing inflammation) 
  10. Gutierrez-Rodrigues et al. Spectrum of clonal hematopoiesis in VEXAS syndrome. Blood 2023;142:244
  11. Gurnari et al. Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort. Am J Hematol 2024;99:254
  12. Kusne et al. Venous and arterial thrombosis in patients with VEXAS syndrome. Blood 2024;143:2190 (40% incidence of VTE)