Acute Promyelocytic Leukemia Harboring STAT5b-RARα Fusion Gene and G596V Mutation in the Stat5b SH2 Domain of the Fusion Gene.

Most patients with acute promyelocytic leukemia (APL) exhibit a characteristic t(15;17) translocation that fuses the PML on 15q22 to the RARα on 17q12. In a small subset of APL, RARα fuses to several other genes including the PLZF on 11q23, NPM1 on 5q35, NUMA1 on 11q13, STAT5b on 17q11, and PRKAR1α on 17q23. The STAT5b-RARα chimeric protein was delocalized from the cytoplasm to the nucleus, where it displayed a microspeckled pattern, implicating that this APL might result from dysregulation of the JAK/STAT5 signal transduction pathway. However, only two patients with APL harboring STAT5b-RARα fusion gene have been reported, and clinical features and response to therapy as well as the pathogenesis in this subgroup remain to be determined. We examined 8 PML-RARα-negative APL patients for the presence of the above alternative fusion genes by RT-PCR. We here present the third patient with APL harboring a STAT5b-RARα fusion gene and a missense mutation G596V in the SH2 domain of the STAT5b. A 41-year old Japanese man admitted to our hospital because of petechiae, fever and leukocytosis (77.8 x 10⁹/L). His promyelocytes were relatively mature with dense nuclei and abundant azurophilic granules, while faggot cells were observed. Promyelocytes were positive for CD13 and CD33, but negative for CD34, CD117 or HLA-DR, consistent with APL cells. Karyotype analysis of the bone marrow cells revealed 47, XY,del(9)(q?),add(17)(q12),+mar1[3]/48, XY,idem,+mar1[17]. Activity of α2 plasmin inhibitor was 16%, and FDP was 344.0 μg/mL (< 5.0 μg/mL). The patient was diagnosed to have APL and DIC with fibrinolysis. He achieved a complete remission after one course of chemotherapy and all-trans retinoic acid (ATRA) although the sign of ATRA-induced granulocytic differentiation was not observed. Sequence analysis of the STAT5b-RARα transcript disclosed that the STAT5-RARα fusion gene corresponded to those of previously reported case of STAT5b-RARα-positive APL. Abnormalities of chromosome 17 and resistance to ATRA were commonly observed in 3 patients harboring STAT5b-RARα. Interestingly, there was an additional missense mutation (G596V) within the STAT5b SH2 domain of the STAT5b-RARα gene. Neither STAT5b-RARα fusion gene nor G596V was detected in marrow cells during remission. As the SH2 domain plays an important role in the activation of STAT proteins and the G596 substituted amino acid is highly conserved in the SH2 domain-containing proteins, it would be interesting to analyze the STAT5b and STAT5b-RARα protein harboring G596V mutation. In addition, G596V mutant clone dominate before treatment and wild type subclone was not detected. G596V mutation may occur at an early phase of leukemogenesis or may acquire dominant proliferation during development of APL. STAT5 appears to upregulate DNA repair protein RAD51. One can assume that activated STAT5b-RARα disrupts DNA repair process and results in genomic instability. Further investigations are needed to understand the molecular pathogenesis and clinical features of STAT5b-RARα-positive APL.