First Description Of a t(10;11)(q22;q23)/MLL-TET1 Reciprocal Translocation In a T Lymphoblastic Lymphoma With Subsequent Lineage Switch To Acute Myelomonocytic Myeloid Leukemia
Authors: Ittel Antoine , Jeandidier Eric , Perrusson Nathalie , Humbrecht Catherine , Lioure Bruno , Mazurier Isabelle , Mayeur-Rousse Caroline , Gervais Carine , Helias Catherine , Thiebault Sylvie , Lerintiu Felix , Mauvieux Laurent 
Published: October 2019

TET1 genomic breakpoints and clinical features of MLL-TET1 rearrangements have been described in 13 acute leukemia cases, 11 in AML, 2 in B cell-precursor ALL. The incidence of this rare translocation was evaluated to 0.3% of MLL rearranged AML cases (5 out of 1590 MLL [Meyer C. Leukemia 2013]). Although those cases are very uncommon, their study can improve our current understanding of leukemogenesis. We report here the first t(10;11) MLL-TET1 positive case of lymphoblastic T lymphoma occurring in a 31 years old male patient, with a subsequent transformation to AML.

The patient was referred for a large mediastinal mass and right pleural effusion. Mediastinal and bronchus biopsies led to the diagnosis of a precursor-T cell lymphoblastic lymphoma, expressing CD3, CD5, CD4, CD8, CD10 antigens, without any expression of CD34 or CD79.

Molecular analyses of the malignant T-cells showed a clonal TCR gamma-chain gene rearrangement together with HOXA10 overexpression. FISH analysis showed a MLL breakage. The partner gene, TET1, was identified using RP11-9E13 and RP11-314J18 BACs, corresponding to the recurrent translocation t(10;11)(q22;q23). MLL-TET1 fusion transcript was detected (intron 8 of TET1 fused to exon 8 of MLL), as well as its reciprocal transcript.

The patient was treated following the (GELA) LL03 protocol, and was considered in complete remission after induction and consolidation phases. Fourteen months after the diagnosis, a bone marrow examination was performed for thrombopenia (6 G/L) which revealed a myelomonocytic acute leukemia with trilineage dysplasia.

At this time, The MLL-TET1 fusion transcript as well as HOXA10 overexpression was still present but the TCR rearrangement was not detected. A non-familial donor allogeneic bone marrow transplant was performed in CR after intensive chemotherapy, that was complicated by a grade IV acute graft-versus-host disease. The patient died 54 days after the transplant of bacterial sepsis leading to multi-organ failure.

MLL-TET1 fusions have been described in 13 cases in the literature, mainly in AMLs (11/13 cases, mostly AML M4 or M5 cases) and in B-ALLs (2/13 cases). The case reported here presents two interesting features. Firstly, this patient harbors the first MLL-TET1 fusion reported to date in T-ALL, and secondly this case presented a lymphoid to myeloid phenotype switch during the time course of the disease.

This strongly suggests that the translocation occurred very early during hematopoietic differentiation, prior to the lymphoid/myeloid commitment. As described for the Ph1 chromosome rearrangement, the t(10;11) translocation may arise in hematopoietic stem cell rather than in committed progenitors. These features are also described in 8p11 stem cell syndrome that involves FGFR1. In both cases, genetic rearrangements arise in myeloid or lymphoid neoplasms with possible subsequent transformation.

TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and play a key role in active DNA demethylation. TET1 and TET2 are also the key enzymes responsible for the presence of 5hmC in mouse embryonic stem cells (ESCs) (Koh KP., Cell Stem Cell 2011), and TET1 functions to regulate the lineage differentiation potential of ESCs. In addition to its role in DNA demethylation, TET1 interacts physically with NANOG and NANOG/TET1 co-occupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells (Costa Y., Nature 2013). Taken together, these observations enlighten possible mechanism of the lineage switch observed in this case, and may be a rationale for using demethylating agents in MLL-TET1 neoplasms.

Disclosures:

No relevant conflicts of interest to declare.