Importance of T-Cell Receptor δ-Chain Gene Analysis on CD7⁺ and CD56⁺ Myeloid/Natural Killer Cell Precursor Acute Leukemia

To the Editor:

Natural Killer (NK) cells differentiate from immature thymocytes under appropriate conditions in vitro and in vivo, and share cytotoxic activity and some surface antigens with T cells, indicating a close relationship with T-lineage.1 Recently, NK cells were found to develop from a population of CD34⁺, CD33⁺, CD56⁻ cells in vitro.1 Suzuki et al2 described six cases of CD7⁺ and CD56⁺ myeloid/NK cell precursor acute leukemia as a distinct hematolymphoid disease entity. Based on Southern blot analysis of immunoassociated genes (except for T-cell receptor [TCR] δ chain) and immunophenotypic and immunohistochemical staining, they neglected association of T-lineage for those cases, because they found germline configuration on Southern blot analysis for only TCR β and γ chain gene but not for TCR δ gene. Cytoplasmic CD3 (cyCD3) was positive in 50% of the cases.

TCR δ rearrangement occurs earlier in T-cell differentiation than that of other TCR genes. So far, δ rearrangement with joining region (J) gene is recognized in only T-cell leukemia or lymphoma but not any other lineage malignancies.3-6 Recently, it was shown that DDJ rearrangements require activation of a T-cell specific enhancer in contrast to VD rearrangements.7Differences in TCR δ gene rearrangement patterns in B-cell precursor acute lymphoblastic leukemia (ALL) and T-cell precursor ALL (T-ALL) can be explained by this finding.

We previously reported the high prevalence of DDJδ in 16 patients with CD7⁺ early T-ALL, which were negative for CD3/4/8/19/20, and myeloperoxidase (MPO).3 Fifteen patients (94%) had rearranged band(s) involving the J region of the TCR δ chain gene. Only DDJδ with no TCR β and γ rearrangement was shown in 9 patients. Four of 9 patients with DDJδ were negative for cyCD3ε. Therefore, it is suggested that DDJδ occurs at an early stage of T-cell differentiation and earlier than expression of cyCD3ε.3 In addition, we reported 6 patients with CD7⁺ early T-ALL/lymphoblastic lymphoma (LBL) which were thought to be transformed from a pro-T I or II cell, indicating T-stem cell leukemia/lymphoma. They had rearrangement in DDJ(5/6) or VDJ(1/6) of TCR δ locus.8 All patients achieved a complete remission. It is of interest that all but 1 had relapsed with a transformation to the mixed phenotype (triphenotype in 3 patients, biphenotype in 2), including myeloid features in 3 patients. The phenotypes we experienced were MPO⁺ in 3 of 5, CD13⁺ in 4 of 5, CD33⁺ in 3 of 5, and CD19⁺ in 3 of 5 patients. In 3 patients we investigated for TCR δ gene, the same δ rearranged band(s) appeared both at the time of diagnosis and relapse, indicating proliferation of the same pro-T leukemic cell clone.8 In addition, our 1 patient with similar characteristics of CD7⁺CD56⁺ myeloid/NK cell precursor acute leukemia reported by Suzuki, showed DDJ recombination, suggesting commitment to T-cell lineage (unpublished data, February 1998). A common T/NK cell progenitor has been noticed in human fetal thymus.1 Analysis of DDJδ in the TCR δ locus should clarify the lineage and clonality of leukemic cells further, even at the stem cell stage of T-cell differentiation.3,6,8 9 From the points described above, TCR δ gene analysis should be performed before myeloid/NK cell precursor acute leukemia is defined and proposed.

We appreciate the comments of Kimura et al, and investigated the T-cell receptor (TCR) δ chain gene status of seven cases of myeloid/natural killer (NK) cell precursor acute leukemia.1-1Our Southern blot analysis with Jδ1 probe showed two cases (nos. 2 and 4) with the Dδ2-Jδ1 and one case (no. 6) with the Dδ2-Dδ3 pattern of TCR δ gene rearrangement (Table 1). The other four cases (nos. 1, 3, 5, and 7) presented a germline configuration of the TCR δ gene which was similar to that seen in a case reported by Ichinohasama et al.1-2 

We think that these results do not necessarily suggest T-cell lineage commitment even in cases no. 2 and 4, as claimed by Kimura et al. First, DDJδ (mostly Dδ2-Jδ1) and VDJδ gene rearrangements of the TCR δ gene have been mentioned in a considerable number of acute myeloid leukemia (AML) cases.1-3 1-4 Thus, the point made by Kimura et al that “δ rearrangement with joining region (J) gene is recognized in only T-cell leukemia or lymphoma but not any other lineage malignancies” is incorrect. Second, TCR δ gene rearrangement was noticed only in one part of a homogeneous clinicopathological disease entity, myeloid/NK cell precursor acute leukemia. Because the lineage identification of a disease should be determined in terms of a broad spectrum of disease properties, including cytochemical, phenotypic, genotypic, histopathologic, and clinical features, the statement that the pro-T cell characteristics can be determined with the aid of the TCR δ gene rearrangement pattern alone is misleading.

TCR δ chain gene rearrangement was first identified as the earliest recombination in T-cell lineage ontogeny, but soon it came to be recognized in B-cell precursor acute lymphoblastic leukemia (ALL) and AML cases. In B-precursor ALL, the rearrangement pattern is characterized by frequent Vδ2-Dδ3 and Dδ2-Dδ3 rearrangements, thus making it different from that in T-cell precursor ALL (T-ALL).1-5 On the other hand, the TCR δ gene rearrangements in AML show the same pattern as those in T-ALL,1-4 and occur more frequently in immature AML^3,6 or in lymphoid antigen–(CD2, CD4, or CD7) positive (Ly+) AML.1-4 Because myeloid/NK cell precursor acute leukemia can be recognized as immature AML or Ly+ AML, the existence of the Dδ2-Jδ1 pattern of TCR δ gene rearrangement in myeloid/NK cell precursor acute leukemia is consistent with reports in the literature.

We therefore maintain our conclusion that myeloid/NK cell precursor acute leukemia constitutes a distinct hematolymphoid disease entity. However, the NK cell precursor is, in a way, a T-cell precursor, because both T cells and NK cells have been shown to be derived from the same myeloid antigen–positive progenitor.1-7 Therefore, TCR δ chain gene rearrangement in myeloid/NK cell precursor acute leukemia might reflect some characteristics of T-cell precursor origin. It might thus be possible for a differentiation pathway of T/NK cell and myeloid lineage to be identified as a result of investigation of the biological significance and underlying mechanism of the TCR δ gene rearrangements in immature AML.