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Acute Myeloid Leukemia |
Medical Clinic and Policlinic I, University Hospital of the Technical University Dresden, Germany
Correspondence: Thomas Illmer, Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Fetscherstrasse 74, 01307 Dresden, Germany. Phone: international +49.351.4584695. Fax: international +49.351.4585362. E-mail: thomas.illmer{at}uniklinikum-dresden.de
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ABSTRACT |
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Key words: JAK2, AML, CBF-leukemias.
Elegant molecular analyses showed a single mutation at amino acid position 617 of the Janus-kinase 2 gene with subsequent activation of tyrosine kinase to be at the origin of myeloproliferative disorders.1,2 Additionally, there is now evidence in the literature that patients with acute myeloid leukemia (AML) with an antecedent myeloproliferative disease often have JAK2 V617F mutations.3
Only recently, a few patients with AML without previous hematologic disorders were found to have the JAK2 V617F mutation.4 It can be assumed that mutations of JAK2 V617F lead to a more aggressive subtype of leukemia because of the activation of the JAK2-STAT5 cascade which substantially alters apoptotic response, self-renewal and proliferative capacity of myeloid cells.5,6 We investigated a large homogenously treated AML population for the presence of the JAK2 V617F mutation.
Patients were included between February 1996 and February 2000 and treated within the German multi-center trial of the SHG AML96 study group. The treatment schedule of the SHG AML96 trial has been published elsewhere.7
JAK2 mutations were investigated by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) method using recently published primers.8 The generic outer primers were labelled with 6-FAM and HEX and PCR products were analyzed on an automated sequencer, essentially as recently described.9 The sensitivity of the assay was determined with a threshold of 1 JAK2 V617F mutated cell in 100 investigated cells. Ten cases of JAK2-V617F mutations were found in 959 AML patients for an overall incidence of 1%. The JAK2 V617F mutations were almost exclusively found in patients with de novo AML (9 out of 785). One other patient with therapy-related AML was affected (1 out of 34). No AML patient with prior myelodysplastic syndrome was found to carry the JAK2 V617F mutation (0 out of 131).
Mutations of JAK2 V617F occurred preferentially in AML patients with karyotypic aberrations (8 out of 476 AML patients with aberrations vs. 1 out of 424 patients without aberrations – p<0.05, karyotype was unknown in 50 patients).
Remarkably, a high proportion of JAK2 V617F positive AML was seen in patients with core binding factor (CBF) leukemias. Whereas 5 out of 138 patients (3.5%) with either t(8;21) (n=2) or inv16 (n=3) proved to be positive for the JAK2 mutation only 5 out of 811 (0.6%) of the remaining AML patients were diagnosed with the mutation (p<0.01).
In contrast to the striking association with aberrant karyotypes no correlation was seen with either age or leukocyte count. We also investigated whether the observed JAK2 mutations coincided with other important molecular alterations in AML. We observed a FLT-3-ITD in one of the patients with the JAK2 mutation whereas none of these patients showed mutations of c-KIT exon 17.
Next, we examined the impact of JAK2 V617F on the prognosis of the patients. To exclude potentially confounding factors and prove an independent impact of JAK2 mutations on survival, we conducted a multivariate analysis (Table 1). The analysis demonstrated a strong independent impact of JAK2 V617F on disease-free survival. This was mainly due to early relapses with nine out of the ten patients with JAK2 V617F relapsing within 20 months after diagnosis. In patients with CBF leukemias overall survival rates were not affected by the presence of the JAK2 V617F mutations. However, we found a remarkable high relapse rate of JAK2V617F patients with either inv(16) or t(8;21) and detected recurrent disease in less than 24 months in four out of five such patients (data not shown) which translated into a lower disease-free surival rate (Figure 1) (p<0.05).
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References |
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TOPABSTRACTReferences |
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. Blood 2006;107:3339-41.
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