Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia

Hassan Awada, Yasunobu Nagata, Abhinav Goyal, Mohammad F. Asad, Bhumika Patel, Cassandra M. Hirsch, Teodora Kuzmanovic, Yihong Guan, Bartlomiej P. Przychodzen, Mai Aly, Vera Adema, Wenyi Shen, Louis Williams, Aziz Nazha, Mohamed E. Abazeed, Mikkael A. Sekeres, Tomas Radivoyevitch, Torsten Haferlach, Babal K. Jha, Valeria VisconteJaroslaw P. Maciejewski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Somatic TET2 mutations (TET2MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2MT includes mostly loss-of-function/ hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2i) in CMML. We speculated that biTET2i might be associated with distinct clinicohematological features. We analyzed TET2MT in 1045 patients with MN. Of 82 biTET2i cases, 66 were biTET2MT, 13 were hemizygous TET2MT, and 3 were homozygous TET2MT (uniparental disomy); the remaining patients (denoted biTET22 hereafter) were either monoallelic TET2MT (n 5 96) or wild-type TET2 (n 5 823). Truncation mutations were found in 83% of biTET2i vs 65% of biTET22 cases (P 5 .02). TET2 hits were founder lesions in 72% of biTET2i vs 38% of biTET22 cases (P, .0001). In biTET2i, significantly concurrent hits included SRSF2MT (33%; P, .0001) and KRAS/NRASMT (16%; P 5 .03) as compared with biTET22. When the first TET2 hit was ancestral in biTET2i, the most common subsequent hits affected a second TET2MT, followed by SRSF2MT, ASXL1MT, RASMT, and DNMT3AMT. BiTET2i patients without any monocytosis showed an absence of SRSF2MT. BiTET2i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET22 patients. Hence, while a second TET2 hit occurred frequently, biTET2i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2i showed lower odds of cytopenias and marrow blasts ($5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2i might represent an auxiliary assessment tool in MN.

Original languageEnglish (US)
Pages (from-to)339-349
Number of pages11
JournalBlood Advances
Volume3
Issue number3
DOIs
StatePublished - Feb 12 2019

ASJC Scopus subject areas

  • Hematology

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