Haematologica, Vol 92, Issue 1, 137-138 doi:10.3324/haematol.10489
Copyright © 2007 by Ferrata Storti Foundation

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Illmer, T. Search for Related Content PubMed PubMed Citation Articles by Illmer, T.

Acute Myeloid Leukemia

Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias

Thomas Illmer, Markus Schaich, Gerhard Ehninger, Christian Thiede on behalf of the DSIL2003 AML study group

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

TOP ABSTRACT References

 
We investigated a large number of acute myeloid leukemia (AML) samples (n=959) for the presence of the JAK2 V617F mutation. We found a low incidence of the mutation in these AML samples (1%). JAK2 V617F mutations clustered in AML samples with an aberrant karyotype (p<0.05). The incidence of JAK2 V617F in patients with a core binding factor (CBF) leukemia was 3.6% (p<0.01). Moreover, JAK2 V617F mutations in CBF leukemias were associated with an aggressive clinical course with 80% of the patients relapsing.

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).

View this table: [in this window] [in a new window] [Download PPT slide]

Table 1. Multivariate analysis for overall survival (OS) and disease-free survival (DFS) using a Cox proportional hazard model.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]

Figure 1. Disease-free survival in patients with CBF-leukemias with wild type (wt) JAK2 vs. JAK2-V617F.

In conclusion, we report a low incidence of JAK2 V617F mutation in patients with in de novo AML in whom the mutation might represent a second hit alteration in leukemogenesis in a particular subset of patients, as indicated by the significant association with cytogenetic aberrations especially with t(8;21) and inv(16). Moreover, the coincidence of the JAK2-mutation with a FLT-3-ITD in one of the patients with a normal karyotype argues for the need for an additional molecular event in the process of transformation into AML. Although the number of patients with JAK2 mutations is small, the abnormality might represent an important additional factor in the assessment of prognosis.

TOP ABSTRACT References

 

1. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144-8.[CrossRef][Medline]
2. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-97.[CrossRef][Web of Science][Medline]
3. Frohling S, Lipka DB, Kayser S, Scholl C, Schlenk RF, Dohner H, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood 2006;107:1242-3.[Free Full Text]
4. Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2006;25:1434-6.[CrossRef][Web of Science][Medline]
5. Ruchatz H, Coluccia AM, Stano P, Marchesi E, Gambacorti-Passerini C. Constitutive activation of Jak2 contributes to proliferation and resistance to apoptosis in NPM/ALK-transformed cells. Exp Hematol 2003;31:309-15.[CrossRef][Web of Science][Medline]
6. Walz C, Crowley BJ, Hudon HE, Gramlich JL, Neuberg DS, Podar K, et al. Activated Jak2 with the V617F Point Mutation Promotes G1/S Phase Transition. J Biol Chem 2006;281:18177-83.[Abstract/Free Full Text]
7. Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schakel U, et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol 2001;112:300-7.[CrossRef][Web of Science][Medline]
8. Jones AV, Silver RT, Waghorn K, Curtis C, Kreil S, Zoi K, et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon . Blood 2006;107:3339-41.[Abstract/Free Full Text]
9. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326-35.[Abstract/Free Full Text]

This article has been cited by other articles:

				E. Iwanaga, T. Nanri, N. Matsuno, T. Kawakita, H. Mitsuya, and N. Asou A JAK2-V617F activating mutation in addition to KIT and FLT3 mutations is associated with clinical outcome in patients with t(8;21)(q22;q22) acute myeloid leukemia Haematologica, March 1, 2009; 94(3): 433 - 435. [Full Text] [PDF]

				T. Akagi, S. Ogawa, M. Dugas, N. Kawamata, G. Yamamoto, Y. Nannya, M. Sanada, C. W. Miller, A. Yung, S. Schnittger, et al. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype Haematologica, February 1, 2009; 94(2): 213 - 223. [Abstract] [Full Text] [PDF]

				J. P. Maciejewski and G. J. Mufti Whole genome scanning as a cytogenetic tool in hematologic malignancies Blood, August 15, 2008; 112(4): 965 - 974. [Abstract] [Full Text] [PDF]

				J. W. Tyner, D. K. Walters, S. G. Willis, M. Luttropp, J. Oost, M. Loriaux, H. Erickson, A. S. Corbin, T. O'Hare, M. C. Heinrich, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2238 - 2245. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Illmer, T. Search for Related Content PubMed PubMed Citation Articles by Illmer, T.