A 48-year-old female presented to the emergency department with severe headaches, dyspnea on exertion, and petechiae on the lower extremities. A CBC was drawn that showed the following: WBC=56 x103/µL, Hgb=9.0 g/dL, Hct=23, MCV=97 fl, plt=15 x109/µL, ANC=0.7x103/µL. A bone marrow biopsy was performed and showed 90 percent lymphoid blasts. The blast population expressed CD19, CD20, CD22, CD10, CD34, TdT, and HLA-DR. Metaphase cytogenetics showed a normal female karyotype. FISH for bcr-abl was positive. The patient was subsequently diagnosed with pre-B acute lymphoblastic leukemia.
The abnormality of which gene is associated with a poor outcome in this patient?
B. Ten-Eleven Translocation-2 (TET2)
E. Isocitrate Dehydrogenase 1/2 (IDH1/IDH2)
IKAROS (IKZF1), a gene located in chromosome 7p12, is responsible for encoding a zinc finger-containing transcription factor called Ikaros that is essential for normal lymphoid development. Using genome-wide analysis, deletions involving IKZF1 were found in 84 percent of 304 patients with acute lymphoblastic leukemia (ALL).1 Ikaros can occur in several splice variants and may explain some of the differential function of this transcription factor. The expression of certain spliced oncogenic Ikaros isoforms in bcr-abl-positive ALL may confer resistance to tyrosine kinase inhibitors (TKIs).2 In a study of 83 patients with bcr-abl-positive ALL, a high frequency of IKZF1 deletions was observed (63 percent), mainly in exons 4 to 7 and exons 2 to 7. Patients who carry the IKZF1 deletions have inferior disease-free survival compared to those who have wild-type IKZF1 (10 months versus 32 months).3
Ten-eleven translocation 2 (TET2) is a gene located in chromosome 4q24. Mutations involving this gene can be found in varying frequencies in myeloid malignancies, including 10 percent in myelodysplastic syndromes, 50 percent in chronic myelomonocytic leukemia (50 percent), 20 percent in myeloproliferative neoplasms (20 percent) and 20 percent in secondary acute myeloid leukemias derived from these conditions. Recent studies suggest that TET2 may be important in epigenetic regulation. The exact prognostic value of this mutation remains unclear although some suggest that patients who have TET2 mutations have a good prognosis.4-6
NOTCH1 is a gene that encodes for a transmembrane receptor that regulates normal T-cell development. This mutation has been detected in > 50 percent of both pediatric and adult T-ALL cases. FBXW7 encodes an E3 ubiquitin ligase responsible for negative regulation of NOTCH1 signaling. Mutations involving FBXW7 occur at a frequency of about 20 percent in ALL. Pediatric studies suggest the good prognostic value of NOTCH1/ FBXW7 mutations. The results in adult ALL patients are less clear, with conflicting results.7-9
Isocitrate Dehydrogenase 1(IDH1) is a gene located in chromosome 2q33.3, while IDH2 is located in chromosome 15q26.1. These genes are responsible for encoding enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarates. Intact IDH activity is necessary for normal cellular protection from oxidative stress. These mutations were first described in low-grade gliomas/secondary glioblastomas and subsequently in acute myeloid leukemia. Some studies suggest that mutations involving this gene may confer poor prognosis in certain subsets, particularly in cytogenetically normal FMS-like tyrosine kinase-3 (Flt-3), wild-type, and nucleophosmin-1 (NPM-1)-mutated AML.10-12
- Mullighan CG, Miller CB, Radtke I, et al. BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110-114.
- Iacobucci I, Lonetti A, Messa F, et al. Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance. Blood. 2008;112:3847-3855.
- Martinelli G, Iacobucci I, Storlazzi CT, et al. IKZF1 (Ikaros) deletions in BCR-ABL1–positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;27:5202-5207.
- Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403-6410.
- Kosmider O, Gelsi-Boyer V, Cheok M, et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood. 2009;114:3285-3291.
- Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23:905-911.
- Asnafi V, Buzyn A, Le Noir S, et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a group for research on adult acute lymphoblastic leukemia (GRAALL) study. Blood. 2009;113:3918-3924.
- Park MJ, Taki T, Oda M, et al. FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol. 2009;145:198-206.
- Mansour MR, Sulis ML, Duke V, et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol. 2009;27:4352-4356.
- Tefferi A, Lasho TL, Abdel-Wahab O, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24:1302-1309.
- Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia (AML): prevalence and prognostic value. Blood. 2010. [Epub ahead of print]
- Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636-3643.
Case study submitted by Sanjay R. Mohan, MD, Cleveland Clinic Taussig Cancer Institute.
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