Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2622-2624
CORRESPONDENCE
Importance of T-Cell Receptor 
-Chain Gene Analysis on
CD7+ and CD56+ Myeloid/Natural Killer
Cell Precursor Acute Leukemia
 |
LETTER |
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] 
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 
and
chain gene but not for TCR gene. Cytoplasmic CD3 (cyCD3) was
positive in 50% of the cases.
TCR rearrangement occurs earlier in T-cell differentiation than
that of other TCR genes. So far, 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.7
Differences in TCR 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 DDJ 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 chain gene. Only DDJ with no TCR and rearrangement was shown
in 9 patients. Four of 9 patients with DDJ were negative for
cyCD3
. Therefore, it is suggested that DDJ occurs at an early
stage of T-cell differentiation and earlier than expression of
cyCD3.3 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 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 gene, the same 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 DDJ in the TCR 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 gene analysis should be performed before myeloid/NK cell
precursor acute leukemia is defined and proposed.
Nobuhiro Kimura
Tetsuya Yoshida
Mitsuyuki Nagano
Kazuo Tamura
First
Department of Internal Medicine, School of Medicine,
Fukuoka
University, Fukuoka, Japan
| |
REFERENCES |
1.
Sanchez MJ,
Muench MO,
Roncarolo MG,
Lanier LL,
Phillips JH:
Identification of a common T/natural killer cell progenitor in human fatal thymus.
J Exp Med
180:569,
1994[Abstract/Free Full Text]
2.
Suzuki R,
Yamamoto K,
Seto M,
Kagami Y,
Ogura M,
Yatabe Y,
Suchi T,
Kodera Y,
Morishima Y,
Takahashi T,
Saito H,
Ueda T,
Nakamura S:
CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: A distinct hematolymphoid disease entity.
Blood
90:2417,
1997[Abstract/Free Full Text]
3.
Kimura N,
Akiyoshi T,
Uchida T,
Okamura J,
Kozuru M,
Nishimura J,
Ohyashiki JH,
Kikuchi M,
Niho Y,
Okumura M:
High prevalence of T-cell receptor D2(D)J rearrangement in CD7+ early T-ALL.
Leukemia
10:650,
1996[Medline]
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4.
Akiyoshi TT,
Kimura N,
Uike N,
Kozuru M,
Tamura K,
Takihara Y,
Hisano S,
Nishimura J,
Kikuchi M:
Genotypic and cytogenetic study of acute myelocytic leukemia and chronic myelocytic leukemia in blast crisis: Specific rearrangement pattern does not involve J gene locus.
Leuk Res
15:683,
1991[Medline]
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5.
Biondi A,
Di Celle PF,
Rossi V,
Casorati G,
Matullo G,
Giudici G,
Foa R,
Migone N:
High prevalence of T-cell receptor V2-(D)-D3 or D1/2-D3 rearrangements in B-precursor acute lymphoblastic leukemias.
Blood
75:1834,
1990[Abstract/Free Full Text]
6.
Breit TM,
Wolvers-Tettero ILM,
Beishuizen A,
Verhoeven MAJ,
Van Wering ER,
Van Dongen JJM:
Southern blot patterns, frequencies, and junctional diversity of T-cell receptor- gene rearrangements in acute lymphoblastic leukemia.
Blood
82:3063,
1993[Abstract/Free Full Text]
7.
Lauzurica P,
Krangel M:
Enhancer-dependent and -independent steps in the rearrangement of a human T cell receptor transgene.
J Exp Med
179:43,
1994[Abstract/Free Full Text]
8.
Nagano M,
Kimura N,
Akiyoshi T,
Nishimura J,
Kozuru M,
Okamura J,
Katsuno M,
Yoshida T,
Takeshita M,
Tachibana K,
Ohshima K,
Kikuchi M:
T-stem cell leukemia/lymphoma with both myeloid lineage conversion and T-specific recombination.
Leuk Res
21:763,
1997[Medline]
[Order article via Infotrieve]
9.
Schmidt CA,
Przybylski G,
Tietze A,
Oettle H,
Siegert W,
Ludwig WD:
Acute myeloid and T-cell acute lymphoblastic leukaemia with aberrant expression exhibit similar TCR gene rearrangements.
Br J Haematol
92:929,
1996[Medline]
[Order article via Infotrieve]
Response
We appreciate the comments of Kimura et al, and investigated the T-cell
receptor (TCR) chain gene status of seven cases of myeloid/natural
killer (NK) cell precursor acute leukemia.1 Our Southern blot analysis with J1 probe showed two cases (nos. 2 and 4) with the D2-J1 and one case (no. 6) with the D2-D3 pattern of TCR gene rearrangement (Table
1). The other four cases (nos. 1, 3, 5, and
7) presented a germline configuration of the TCR gene which was
similar to that seen in a case reported by Ichinohasama et
al.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, DDJ (mostly D2-J1) and VDJ gene
rearrangements of the TCR gene have been mentioned in a
considerable number of acute myeloid leukemia (AML)
cases.3,4 Thus, the point made by Kimura et al that "
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 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 gene
rearrangement pattern alone is misleading.
TCR 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 V2-D3 and D2-D3 rearrangements, thus making it different from that in T-cell precursor ALL
(T-ALL).5 On the other hand, the TCR gene
rearrangements in AML show the same pattern as those in
T-ALL,4 and occur more frequently in immature
AML3,6 or in lymphoid antigen-(CD2, CD4, or CD7) positive
(Ly+) AML.4 Because myeloid/NK cell precursor acute
leukemia can be recognized as immature AML or Ly+ AML, the existence of
the D2-J1 pattern of TCR 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.7 Therefore,
TCR 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 gene rearrangements in immature AML.
Ritsuro Suzuki
Masao Seto
Yasuo Morishima
Shigeo Nakamura
Laboratory of
Chemotherapy
Department of Hematology and Chemotherapy
Department
of Pathology and Clinical Laboratories
Aichi Cancer Center, Nagoya,
Japan
| |
REFERENCES |
1.
Suzuki R,
Yamamoto K,
Seto M,
Kagami Y,
Ogura M,
Yatabe Y,
Suchi T,
Kodera Y,
Morishima Y,
Takahashi T,
Saito H,
Ueda R,
Nakamura S:
CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia: A distinct hematolymphoid disease entity.
Blood
90:2417,
1997
2.
Ichinohasama R,
Endoh K,
Ishizawa K,
Okuda M,
Kameoka J,
Meguro K,
Myers J,
Kadin M,
Mori S,
Sawai T:
Thymic lymphoblastic lymphoma of committed natural killer cell precursor origin.
Cancer
77:2592,
1996[Medline]
[Order article via Infotrieve]
3.
Fontenay M,
Flandrin G,
Baurman H,
Loiseau P,
Valensi F,
Daniel M-T,
Sigaux F:
T cell receptor gene rearrangements occur predominantly in immature myeloid leukemias exhibiting lineage promiscuity.
Leukemia
4:100,
1990[Medline]
[Order article via Infotrieve]
4.
Schmidt CA,
Przybylski G,
Seeger K,
Siegert W:
TCR chain gene rearrangements in acute myeloid leukemia with T-lymphoid antigen expression.
Leuk Lymphoma
20:45,
1995[Medline]
[Order article via Infotrieve]
5.
Breit TM,
Wolvers-Tettero ILM,
Beishuizen A,
Verhoeven MAJ,
van Wering ER,
van Dongen JJM:
Southern blot patterns, frequencies, and junctional diversity of T-cell receptor- gene rearrangements in acute lymphoblastic leukemia.
Blood
82:3063,
1993
6.
Schmidt CA,
Oettle H,
Neubauer A,
Seeger K,
Thiel E,
Huhn D,
Siegert W,
Ludwig WD:
Rearrangements of T-cell receptor delta, gamma and beta genes in acute myeloid leukemia coexpressing T-lymphoid features.
Leukemia
6:1263,
1992[Medline]
[Order article via Infotrieve]
7.
Sanchez MJ,
Muench MO,
Roncarolo MG,
Lanier LL,
Phillips JH:
Identification of a common T/natural killer cell progenitor in human fetal thymus.
J Exp Med
180:569,
1994
