Sideroblastic anemia associated with abnormal clone formation such as myelodysplastic and myeloproliferative conditions has historically been termed pre-leukemia, refractory anemia, or even idiopathic with no known cause. With the development and progression of molecular diagnostics much has been learned about genetics resulting in reclassifications.
Rodriguez-Sevilla, Calva, and Arnillas wrote in PubMed Central Causes and Pathophysiology of Acquired Sideroblastic Anemia (2022)21 in which they identified the genetic and phenotypic characteristics of congenital and acquired sideroblastic anemia, adapted from Ducamp, et al.22
Genes associated with clonal sideroblastic anemia are SF3B1, JAK2, CALR, and MPL.
Myelodysplastic Syndromes with Ring Sideroblasts (MDS-RS) is the most common acquired sideroblastic anemia characterized by cytopenias, morphological dysplasia, and 15% or more erythroid ring sideroblasts in the bone marrow, or more than 5% if associated with the SF3B1 mutation. There are two subgroups of MDS-RS.
- Myelodysplastic Syndrome with Ring Sideroblast - single lineage (MDS-RS-SLD) involves a change in only one cell line.
- Myelodysplastic Syndrome with Ring Sideroblast - multilineage (MDS-RS-MLD) involves dysplasia in more than two myeloid cell lines. Of the two subgroups, MDS-RS-MLD is more common.
In addition to the two previously mentioned subgroups, either form of MDS-RS that presents with isolated del(5q) will be classified as Myelodysplastic Syndrome with Ring Sideroblasts with Excess Blasts indicating the condition is in transition to becoming an acute condition. These patients will exceed 1% blasts in the peripheral blood and 5% blasts in the bone marrow. They may or may not present with SF3B1 mutation.21
Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) was identified in the 2016 WHO classification. Patients will present with erythroid dysplasia. Other cell lines may or may not be involved, however, the platelet count is high, over 450.0 X 109/L, and 15% or more ring sideroblasts are found in the bone marrow.22 In addition, one expects to find large, atypical megakaryocytes and mature megakaryocytes with hyperlobed nuclei. BCR-ABL1, PDGRA, PDGFRB, FGR1, and PCM1-JAK2 rearrangements will be absent. Finally, t(3;3), (q21q26), inv(3)(q21q26) or del(5q) must be absent for the diagnosis.23
Primary Myelofibrosis (PM) may present with ring sideroblasts. SF3B1 mutations have been present in some cases.24
Acute Myeloid Leukemia (AML) may present with ring sideroblasts, and SF3B1 mutations are uncommon.25
21. Rodriguez-Sevilla JJ, Calvo X, Arenillas L. "Causes and Pathophysiology of Acquired Sideroblastic Anemia." Genes (Basel). 2022 Aug 30;13(9):1562. https://pubmed.ncbi.nlm.nih.gov/36140729/.22. Ducamp S., Fleming M.D. "The molecular genetics of sideroblastic anemia." Blood. 2019;133:59–69, https://pubmed.ncbi.nlm.nih.gov/30401706/.23. Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Volume 2 International Agency for Research on Cancer; Lyon, France: 2017.24. Lasho T.L., Finke C.M., Hanson C.A., Jimma T., Knudson R.A., Ketterling R.P., Pardanani A., Tefferi A. "SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients."Leukemia. 2012;26:1135–1137, https://pubmed.ncbi.nlm.nih.gov/22064353/.25. Berger G., Gerritsen M., Yi G., Koorenhof-Scheele T.N., Kroeze L., Stevens-Kroef M., Yoshida K., Shiraishi Y., Berg E.V.D., Schepers H., et al. "Ring sideroblasts in AML are associated with adverse risk characteristics and have a distinct gene expression pattern." Blood Adv. 2019;3:3111–3122, https://pubmed.ncbi.nlm.nih.gov/31648334/.
