Figure 2.
Illustration of the clonal architecture of hematopoietic cell populations from 5 patients. (A) Identical TET2 and DNMT3A mutations were detected in the FC-sorted neoplastic T cells (AITL), normal granulocytes, and normal B cells from the BM of patient 13, suggesting origin of all populations from a shared HSPC precursor harboring TET2 and DNMT3A mutations. This sequenced BM did not meet World Health Organization criteria for diagnosis of a MN. (B) Patient 2 developed MDS with a complex karyotype 2 years after being diagnosed with AITL. Identical DNMT3A and 2 TET2 mutations were identified in the FC-sorted neoplastic T cells from the patient’s original AITL staging BM (obtained 2 years prior to development of MDS) and the bulk BM obtained at the time of the MDS diagnosis (which showed no involvement by AITL), consistent with origin of both neoplasms from a common TET2- and DNMT3A-mutated HSPC precursor. Alterations limited to the AITL included RHOA, IDH2, ATR, and KMT2B mutations, while those limited to the MDS included CEBPA and RUNX1 mutations, consistent with the acquisition of separate and divergent genomic events in each neoplasm. (C) Patient 2 also had a history of smoldering plasma cell (PC) myeloma diagnosed 14 months prior to his AITL. FC sorting of neoplastic T cells and plasma cells and fluorescence in situhybridization analysis of enriched CD138+ plasma cells from his staging BM sample at the time of AITL diagnosis demonstrated differing sets of genetic alterations in each population, consistent with 2 unrelated neoplastic processes. (D) Patient 10 developed AML 2.7 years after his AITL diagnosis. FC-sorted leukemic myeloid blasts and neoplastic T cells from BM shared 2 TET2 mutations and 1 DNMT3A mutation. Alterations limited to the AML included del(7q), a RUNX1 mutation, and an additional DNMT3A mutation, while the AITL harbored a number of mutations (including ARID1B and ROBO1) and gain of chromosome 3 not seen in the AML. (E) Patient 11 developed MDS-EB-1 3.6 years after being diagnosed with AITL. Bulk AITL tissue and FC-sorted neoplastic BM myeloid blasts shared 2 TET2 mutations and 1 DNMT3A mutation; the same TET2 mutations were also identified in FC-sorted normal lymphocytes. Alterations limited to the neoplastic myeloid population included an inv(3), while only the neoplastic T cells had an EPHA5 mutation. (F) Patient 22 developed CMML-0 2.7 years after being diagnosed with AITL. Comparison of VAFs from bulk BM (negative for AITL) and tissue samples demonstrated 2 shared TET2 mutations in AITL and CMML. Only CMML harbored a SRSF2 mutation, while the AITL harbored a number of additional mutations (including an additional TET2 mutation) not identified in CMML. MDS, myelodysplastic syndrome.

Illustration of the clonal architecture of hematopoietic cell populations from 5 patients. (A) Identical TET2 and DNMT3A mutations were detected in the FC-sorted neoplastic T cells (AITL), normal granulocytes, and normal B cells from the BM of patient 13, suggesting origin of all populations from a shared HSPC precursor harboring TET2 and DNMT3A mutations. This sequenced BM did not meet World Health Organization criteria for diagnosis of a MN. (B) Patient 2 developed MDS with a complex karyotype 2 years after being diagnosed with AITL. Identical DNMT3A and 2 TET2 mutations were identified in the FC-sorted neoplastic T cells from the patient’s original AITL staging BM (obtained 2 years prior to development of MDS) and the bulk BM obtained at the time of the MDS diagnosis (which showed no involvement by AITL), consistent with origin of both neoplasms from a common TET2- and DNMT3A-mutated HSPC precursor. Alterations limited to the AITL included RHOA, IDH2, ATR, and KMT2B mutations, while those limited to the MDS included CEBPA and RUNX1 mutations, consistent with the acquisition of separate and divergent genomic events in each neoplasm. (C) Patient 2 also had a history of smoldering plasma cell (PC) myeloma diagnosed 14 months prior to his AITL. FC sorting of neoplastic T cells and plasma cells and fluorescence in situhybridization analysis of enriched CD138+ plasma cells from his staging BM sample at the time of AITL diagnosis demonstrated differing sets of genetic alterations in each population, consistent with 2 unrelated neoplastic processes. (D) Patient 10 developed AML 2.7 years after his AITL diagnosis. FC-sorted leukemic myeloid blasts and neoplastic T cells from BM shared 2 TET2 mutations and 1 DNMT3A mutation. Alterations limited to the AML included del(7q), a RUNX1 mutation, and an additional DNMT3A mutation, while the AITL harbored a number of mutations (including ARID1B and ROBO1) and gain of chromosome 3 not seen in the AML. (E) Patient 11 developed MDS-EB-1 3.6 years after being diagnosed with AITL. Bulk AITL tissue and FC-sorted neoplastic BM myeloid blasts shared 2 TET2 mutations and 1 DNMT3A mutation; the same TET2 mutations were also identified in FC-sorted normal lymphocytes. Alterations limited to the neoplastic myeloid population included an inv(3), while only the neoplastic T cells had an EPHA5 mutation. (F) Patient 22 developed CMML-0 2.7 years after being diagnosed with AITL. Comparison of VAFs from bulk BM (negative for AITL) and tissue samples demonstrated 2 shared TET2 mutations in AITL and CMML. Only CMML harbored a SRSF2 mutation, while the AITL harbored a number of additional mutations (including an additional TET2 mutation) not identified in CMML. MDS, myelodysplastic syndrome.

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