May 2014, Vol 3, No 3

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JAK2 V617F in a Patient With AML


PMO is pleased to offer the department “The Biomarker” to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact and clinical decision-making implications of that marker.

Do you have a unique case to share with our reading community? Please submit your biomarker-driven cases to us at

Pranil K. Chandra, DO, is Director, Molecular Pathology Services and Interim Medical Director, Clinical Pathology of PathGroup.

Jason Gottwals is Director of Training & Technical Marketing at PathGroup.

Thank you for returning to read the second installment of “The Biomarker,” a column to discuss the diagnostic, prognostic, and/or clinical applications of biomarkers in patients with cancer. This month we have a guest author, Jason Gottwals, who will be highlighting a very intriguing case. Jason is the technical director of marketing and provides leadership to the scientific training of our sales force at PathGroup.

Our patient presented with pancytopenia and underwent a diagnostic bone marrow biopsy and ancillary studies. Routine morphologic examination and flow cytometric analysis confirmed acute myeloid leukemia (AML). Conventional and molecular (fluorescence in situ hybridization [FISH]-based) karyotyping demonstrated an interstitial deletion on the long arm of chromosome 7. FISH studies also revealed a deletion in 20q. Polymerase chain reaction (PCR) and next-generation molecular studies were negative for common mutations seen in AML, including FLT3, KIT, CEBPA, NPM1, IDH1, IDH2, PHF6, and DNMT3A. The sole mutation identified was a JAK2 V617F mutation by targeted next-generation sequencing.

The JAK-STAT Pathway in Molecular Oncologic Practice
The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to target gene promoters in the nucleus, providing a mechanism for transcriptional regulation without secondary messengers.1 A variety of cytokines and growth factors complete their physiological tasks through the JAK-STAT pathway, including hematopoiesis, immune regulation, fertility, lactation, growth, and embryogenesis.2 The activating mutation V617F of JAK2 tyrosine kinase is well documented and present in the majority of patients with polycythemia vera (97%), with subsequently declining incidence in essential thrombocythemia (57%) and primary myelofibrosis (50%).3,4 These myeloproliferative disorders are characterized by overactive hematopoiesis, with the major feature of poly­cythemia vera and essential thrombocythemia being increased production of red cells and platelets, respectively. Deletion of 20q has also been associated with myeloproliferative myeloid stem cell disorders.

AML: Another Heterogeneous Disease on a Molecular Level
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition, from the World Health Organization (WHO), remains the standard text for diagnosis and classification of AML for hematopathologists. The WHO classification of AML integrates clinical features with morphology, flow cytometric immunophenotyping, conventional and molecular (FISH-based) cytogenetics, and PCR-based studies to guide diagnosis, prognosis, and therapeutic managment.5 High-throughput sequencing technologies have transformed the practice of hematopathology by being able to rapidly identify genomic aberrations that yield prognostic and therapeutic information. Recent work on AML demonstrated clonal heterogeneity that evolves upon disease progression and/or relapse.6 Surprisingly, a large number of these alterations appear to be in genes whose function is known, or suspected, to be involved in epigenetic regulation of gene transcription. In the April issue of PMO, there was a nice review of the clinical significance of FLT3 ITD mutations in AML,7 which is associated with an aggressive clinical course. Recent work has implicated other genes such as IDH1, IDH2, DNMT3A, PHF6, RUNX1, and TP53 to have diagnostic, prognostic, and/or therapeutic significance. For example, AML with a PHF6 mutation has an aggressive clinical course, whereas the presence of an NPM1 or IDH1 mutation as the sole mutational abnormality is associated with a relatively favorable outcome. Furthermore, AML with mutations in MLL, DNMT3A, and/or NPM1 appear to benefit from high-dose induction chemotherapy.8

JAK2 V617F in AML: Implications for Precision Oncology
A 2007 study by Vicente and colleagues screened 10 AML cell lines and 339 patients for the presence of the JAK2 V617F mutation and found an overall incidence of 3.2%, with all mutations documented in M1 or M2 subtypes, suggesting a correlation with less differentiated leukemias.9 This research mirrored previous studies by Lee et al and Steensma et al in 2006, who found JAK2 V617F mutations in 2.7% and 8% of AML cases, respectively. In both studies, V617F mutation was seen more commonly in transformed myeloproliferative disease, although both studies identified de novo AML with V617F as well.10,11 The detection of a JAK2 mutation as well as the 20q deletion in this patient is highly suggestive of a background myeloproliferative or myelodysplastic/myeloproliferative disorder. Studies have demonstrated that AML arising in the background of chronic-phase myeloid stem cell disorders are distinct from de novo AML both genetically and clinically. This notion is supported by observed resistance to conventional antileukemic therapeutic regimens.12 Multiple pharmacotherapeutic agents are currently at various stages of development targeting the JAK-STAT pathway.13

AML is extremely heterogeneous on a molecular level, and research continues to identify new and exciting genomic aberrations that have clinical utility. Mutations in the JAK-STAT pathway are, as a whole, rare in AML; however, advancement in targeted therapies may provide additional benefit when combined with conventional cytotoxic regimens in this aggressive disease course.14 Clinical management decisions in AML in the near term will continue to rely on a foundation established by the WHO guidelines; however, modern technologies such as next-generation sequencing have enormous potential to inform prognosis and result in increased precision with regard to risk stratification. This information, in turn, will allow for more precise and scientifically driven treatment planning and hopefully improved outcomes in this highly deadly disease. Indeed, the era of precision oncology is upon us in the setting of AML.

1. Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science. 2002;296:1653-1655.
2. Furqan M, Mukhi N, Lee B, et al. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res. 2013;1:5.
3. Ihle JN, Gilliland DG. Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev. 2007;17:8-14.
4. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.
5. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. World Health Organization. Lyon, France: IARC; 2008.
6. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506-510.
7. Lewis MJ. Case study: molecular profiling in acute myeloid leukemia. Personalized Medicine in Oncology. 2014;3:86-87.
8. Fathi AT, Abdel-Wahab O. Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. Adv Hematol. 2012;2012:469592.
9. Vicente C, Vázquez I, Marcotegui N, et al. JAK2-V617F activating mutation in acute myeloid leukemia: prognostic impact and association with other molecular markers. Leukemia. 2007;21:2386-2390.
10. Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene. 2006;25:1434-1436.
11. Steensma DP, McClure RF, Karp JE, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia. 2006;20:971-978.
12. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol. 2014;21:65-71.
13. My Cancer Genome. Anticancer agents. Accessed April 22, 2014.
14. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614-4618.

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