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KANK1, a Candidate Tumor Suppressor Gene, Is Fused to PDGFRB in an Imatinib-Responsive Myeloid Neoplasm with Severe Thrombocythemia

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KANK1, a Candidate Tumor Suppressor Gene, Is Fused to PDGFRB in an Imatinib-Responsive Myeloid Neoplasm with Severe Thrombocythemia Letters to the Editor 1052 the secondary malignancies and cardiovascular events, may not 2 Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ directly relate to SCT itself. et al. Comparative outcome of reduced intensity and Long-term follow-up should also consider issues of quality of myeloablative conditioning regimen in HLA identical sibling life (QOL). This initial analysis shows that chronic graft-versus- allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a host disease rates and the duration of required immune retrospective survey from the Acute Leukemia Working Party suppression were lower after RIC. Chronic graft-versus-host (ALWP) of the European group for Blood and Marrow Transplanta- disease is a dominant factor determining QOL, suggesting better tion (EBMT). Leukemia 2005; 19: 2304–2312. long-term QOL with RIC; however, formal QOL assessment is 3 Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, required to determine this question. Finke J et al. Retrospective comparison of reduced-intensity The major limitation of this study is the nonrandomized conditioning and conventional high-dose conditioning for allo- geneic hematopoietic stem cell transplantation using HLA- comparison and the selection biases in allocating patients to one identical sibling donors in myelodysplastic syndromes. Blood of the regimens. However, because patients were selected for 2006; 108: 836–846. RIC based on high risk for non-relapse mortality, and because 4 Ringde´n O, Labopin M, Ehninger G, Niederwieser D, Olsson R, OS was similar among these patients given RIC and eligible Basara N et al. Reduced intensity conditioning compared with patients given MAC, it is possible that results in standard risk myeloablative conditioning using unrelated donor transplants in patients may be similar. Randomized studies, for patients in CR patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 4570– 4577. (preferentially CR1) with long-term follow-up and assessment of 5 Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, late complication and QOL, will be needed to determine the Avigdor A et al. Allogeneic hematopoietic stem-cell transplantation best approach in this setting. MAC and possibly the new in AML and MDS using myeloablative versus reduced-intensity reduced toxicity myeloablative regimens are still the best conditioning: the role of dose intensity. Leukemia 2006; 20: 322– approach in patients with active disease. 328. 6 Socie´ G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, Bredeson C et al. Long-term survival and late deaths after allogeneic Conflict of interest bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 1999; 341: 14–21. The authors declare no conflict of interest. 7 Mohty M, de Lavallade H, El-Cheikh J, Ladaique P, Faucher C, Fu¨rst S et al. Reduced intensity conditioning allogeneic stem cell A Shimoni, I Hardan, N Shem-Tov, R Yerushalmi transplantation for patients with acute myeloid leukemia: long term and A Nagler results of a ‘donor’ versus ‘no donor’ comparison. Leukemia 2009; The Division of Hematology and Bone Marrow 23: 194–196. Transplantation, Chaim Sheba Medical Center, 8 Valca´rcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB Tel-Hashomer, Israel et al. Sustained remissions of high-risk acute myeloid leukemia and E-mail: [email protected] myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577–584. References 9 Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H et al. Treatment for acute myelogenous leukemia 1 Blaise D, Vey N, Faucher C, Mohty M. Current status of reduced- by low-dose, total-body, irradiation-based conditioning and hemato- intensity-conditioning allogeneic stem cell transplantation for acute poietic cell transplantation from related and unrelated donors. myeloid leukemia. Haematologica 2007; 92: 533–541. J Clin Oncol 2006; 24: 444–453. KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia Leukemia (2010) 24, 1052–1055; doi:10.1038/leu.2010.13 of myeloproliferative neoplasm, most likely essential thrombo- published online 18 February 2010 cythemia. There was no detectable BCR–ABL transcript or JAK2 V617F mutation, which is present in about 50% of patients with essential thrombocythemia. The karyotype performed on bone The majority of myeloproliferative neoplasms are associated marrow cells showed 46,XY,t(5;9)(q31B32;p22B?24.3) in 16 with activating mutations in protein tyrosine kinase genes.1 of 18 metaphases (Figure 1a). Treatment with hydroxyurea was About 20 different fusion products of the PDGFRB gene, which started, but elicited no response. After two-and-a-half months of encodes platelet-derived growth factor receptor-b (PDGFRb), treatment, the platelet count had increased to 1400 Â 109/l and have been described in patients with myeloid neoplasms the neutrophil and eosinophil counts to 13 Â 109/l and associated with eosinophilia.1,2 Myelodysplastic features 0.9 Â 109/l, respectively. The patient experienced a transient and thrombocytopenia are often associated with PDGFRB ischemic attack that was attributed to the thrombocythemia. translocations.3 Fluorescence in situ hybridization analysis established the Here, we describe a new acquired t(5;9) chromosomal disruption of the PDGFRB locus. As this tyrosine kinase receptor translocation in a 67-year-old male patient who presented with is highly sensitive to imatinib mesylate,2,3 the patient was thrombocythemia (platelets, 904 Â 109/l) without prominent treated with a low dose of this drug (100 mg/day). At 4 months eosinophilia or neutrophilia. Bone marrow smears showed an after the initiation of this treatment, platelet and leukocyte increased number of polymorphic megakaryocytes without any counts were back to normal levels (Figure 1b). After 12 months blast cells or dysplastic features. Morphology was suggestive of follow-up, the patient remains in complete hematological Leukemia Letters to the Editor 1053 Figure 1 The t(5;9) translocation implicates KANK1 as a new fusion partner to PDGFRB in a patient with imatinib-sensitive thrombocythemia. (a) G-banded partial karyotype of the patient showing the t(5;9). (b) Evaluation of the patient’s platelet counts (continuous line) and white blood cell counts (dashed line) as a function of time. Arrows indicate when the treatments were initiated (HU, hydroxyurea). (c) The RNA and protein sequences of the KPb breakpoint are shown. (d)KPb expression was analyzed by nested RT-PCR in cDNA derived from bone marrow samples from the patient with the t(5;9)-positive myeloid neoplasm (lane 2), or from patients with chronic myelogenous leukemia (lanes 3 and 4) or with acute lymphoblastic leukemia (lane 5). (e) A schematic representation of KANK1, PDGFRb and KANK1–PDGFRb (KPb) proteins is shown. cc, coiled-coil domain; A, ankyrin domain; octagons in PDGFRb represent Ig-like domain; TM, transmembrane domain; and Kinase, kinase domain. The position of the breakpoint is indicated by arrowheads. Localization of the two primer sets used in nested PCR (d) is represented by arrows. remission. The response to low-dose imatinib pointed to could be cultured for several weeks in the absence of IL-3 (data constitutive activation of PDGFRb as the cause of thrombo- not shown), indicating that KPb is able to transform hemato- cythemia in this patient. poietic cells. To evaluate KPb sensitivity to imatinib mesylate, Using rapid amplification of cDNA ends PCR, we identified Ba/F3–KPb cells were exposed to increasing concentrations of the KANK1 gene (also called ANKRD15) on chromosome 9 as the drug, which inhibited cell growth in the absence of IL-3 the fusion partner of PDGFRB (Figure 1c). The fusion was (Figure 2b). The estimated IC50 for KPb was around 7 nM, which confirmed by fluorescence in situ hybridization using specific corresponded to the reported values for ETV6–PDGFRb and KANK1 probes (Supplementary Figure S1) and by nested PCR FIP1L1–PDGFRa inhibition, and is about two orders of (Figure 1d), as described in Supplementary Materials and magnitude lower than the concentration required to inhibit methods. The translocation fuses exon 2 of KANK1 BCR–ABL.2 (ENST00000382293, Ensembl database, up to nucleotide Autophosphorylation of tyrosine residues in the intracellular 3020) to exon 9 of PDGFRB (ENST00000261799, from part of receptor tyrosine kinases is a critical step to achieve nucleotide 1714). The junction with exon 9 of PDGFRB is their full activation.2 After immunoprecipitation of PDGFRb- unusual and was mentioned only once regarding an containing proteins, we showed that KPb was constitutively ETV6–PDGFRB fusion (unpublished data in Curtis et al4). In tyrosine phosphorylated in Ba/F3 cells (Figure 2c). As expected, line with several previously reported PDGFRb hybrids, KANK1– this was not observed in the presence of imatinib, suggesting PDGFRb (KPb) contains three coiled-coil domains of KANK1, that KPb phosphorylated itself. STAT transcription factors are which may mediate the oligomerization of the hybrid protein, downstream targets of the PDGF receptors.2 Aberrant activation as shown for wild-type KANK1.5 It also includes the fifth of STAT5 has an important role in hematopoietic cell immunoglobulin (Ig)-like extracellular domain, the transmem- transformation by many tyrosine kinase oncogenes, including brane domain and the kinase domain of PDGFRb (Figure 1e). ETV6–PDGFRB.2 By western blot with specific anti-phospho-site The KANK1 gene was identified as a potential tumor antibodies, we showed that STAT5, as well as the related factor suppressor gene at 9p24, whose expression was lost in renal STAT3, were phosphorylated in the presence of KPb in an cell carcinoma tissues and cell lines. The 9p chromosomal imatinib-dependent manner (Figure 2d).
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