Abstract
Introduction: Four families are reported to have hereditary thrombocythemia (HT) with a mutation in TPO. Their clinical manifestation is essentially thrombocytosis without leukemia. CML is one of myeloproliferative disorders, and shows leukocytosis and thrombocytosis associated with a proliferation of malignant clone originated from a hematopoietic stem cell (HSC). The incidence of CML is about 5 per 100,000 in Japan. Mutations of cytokine receptor including c-kit, flt-3 and G-CSF receptor are reported as a cause of AML. Especially flt-3 abnormalities are found in about 20% of AML. However, abnormality of c-mpl or TPO is not reported as a cause of leukemia. In this paper, we analyzed a CML case with novel point mutation in the TPO who still had thrombocytosis after cytogenetic complete response.
Case: Japanese, 35 y.o., male, complained leukocytosis. He had a family history of thrombocytosis in 4 individuals over 3 generations. A physical examination revealed a moderate splenomegaly. Laboratory tests at the time of diagnosis were as follows; WBC 141,000/μl (blast 1.8%, promyelo 2.4%, myelo 20.0%, meta 8.2%, stab 24.2%, seg 22.2%, immature eosinophils 1.8%, eosinophil 3.6%, immature basophils 0.4%, basophils 10.4%, mono 1.0%, lymphocytes 4.0%, erythroblast 3%), PLT 641,000/μl and NAP score 53 (nl; 156–271). Bone marrow showed hypercellularity with the increased megakaryocytes(Meg), bcr-abl fusion mRNA positive, Ph1 chromosome positive. After 5 months treatment with STI571, most of clinical findings including karyotype and fusion mRNA turned to be normal, but thrombocyte(PLT) still showed more than 1,000,000/μl. At this time, serum TPO concentration was 8.14 f mole/ml (nl; 0.40 +/− 0.28 f mole/ml, mean +/− SD). Genetic analysis of TPO revealed novel point mutation at splicing donor site of 3′-end of the exon3. A point mutation at splicing donor site is reported to cause an exon-skipping and intron-retention, which induce a malfunction of a suppressive post-transcriptional and translational regulation, and consequent high-level expression of functional TPO protein.
Discussion: TPO was cloned as a c-mpl ligand, which leads to the production of PLTs. Its receptor is a c-mpl proto-oncogene product, which is expressed not only in Meg, but also in HSC. Thus, TPO can stimulate HSC. The c-mpl transgenic mice are reported to have the increased Meg, its committed progenitor and PLT. Knockout mice of TPO presented not only the decreased Meg, but also multi-lineage committed progenitors. Thus, a modulation of c-mpl or its ligand function affects on both Meg and HSC. The c-mpl was cloned as a cellular homolog of a viral oncogene, v-mpl of myeloproliferative leukemia virus (MPL). The MPL causes myeloproliferative leukemia syndrome through v-mpl function in mice. Since v-mpl and c-mpl indicate high homology, it is possible that abnormal c-mpl function causes v-mpl like response. Through continuous stimulation of c-mpl signal, high TPO concentration may have induced a malignant transformation of HSC or supported a survival of an immature malignant clone in the present case. Improvement of thrombocytosis in CML is one of hematological responses to an anti-CML treatment such as STI571. In such a case who had good response other than thrombocytosis, an existence of HT might be considered. On the other hand, during following up HT family, occurrence of CML should be noted.
Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1