Contribution of GM-CSF and IL-8 to the CD44-induced differentiation of acute monoblastic leukemia

Letters to the Editor 873 Alternatively, although not previously reported in patients with JAK2 exon 12 mutations, the patient may have a proportion of cells in the PBMNC population in which both alleles are mutated. While we have detected an identical JAK2 mutation in two patients (PV31 and PV63) and a similar mutation in patient PV64, disease presentation and progression varied considerably between the patients (Table 1). PV31 presented with mildly elevated haemoglobin (Hgb) at an early age (32 years). The average age of diagnosis of JAK2V617F-positive patients in our cohort is 63.05711.85 years, range 40–84 years (n ¼ 40). Bone marrow cytogenetic analysis was normal, although the marrow was hypercellular with mild dysplastic changes of the megakaryocytes. Thromboembolic complications or other evidence of progressive disease remained absent in this patient 4 years after PV diagnosis. Patient PV63 had pre-existing chronic obstructive lung disease and presented at age 84 years with markedly elevated haemoglobin. The patient was started on regular venesections but developed deep-vein thrombosis (DVT) after 2 months. Of note, platelet levels were increasing during this time (from 310 to 618
109 l1), although the patient developed iron deficiency, presumably due to the phlebotomy therapy. Hydroxyurea and warfarin anticoagulation therapy resolved the DVT and blood counts normalized upon cessation of venesections, however the patient died as a result of respiratory failure 6 months after PV diagnosis without evidence of pulmonary embolism. The diagnosis of PV in this patient had been made without a BM biopsy but, interestingly, a trephine taken 4 years earlier to investigate pyrexia of unknown origin showed trilineage hyperplasia, small megakaryocyte clusters located close to the trabeculae and mild fibrosis. This is consistent with progression of the MPD to clinically symptomatic disease over a number of years. Patient PV64 presented at 68 years of age with marked erythrocytosis. Interestingly, this patient was thrombocytopenic at presentation and this persisted throughout the course of the disease despite steroid therapy (platelet count varied between 18–119
109 l1). Approximately 2 years after presentation, the patient developed marked leukocytosis (WCC 24.0
109 l1). A BM biopsy at this time was hypercellular with some dysplastic features, although megakaryocytes were decreased, consistent with the thrombocytopenia seen in this patient. A second BM biopsy, 2 months later (which provided the sample for this study) showed similar findings and with moderate fibrosis reported. The patient progressed to development of acute myeloid leukaemia (AML) within one year and died some months later. Thus, while PV31 and several other patients reported with JAK2 exon 12 mutations are of early onset and generally present with platelet, leukocyte and granulocyte counts within the normal range,4,5 patients PV63 and PV64 presented with multilineage disease of late onset associated with thrombo-embolic complications (DVT) and rapid transformation to AML, respectively. Furthermore, other modifying factors extrinsic to the haematopoietic system such as coexistent lung disease and chronic inflammation, may be important in the manifestation of disease involving JAK2 exon 12 mutations and, as suggested by Pardanani et al.,5 the specific classification of disease based on alternative JAK2 mutations should be carefully considered as further patients are described. CM Butcher1, U Hahn2, LB To3, J Gecz4, EJ Wilkins5, HS Scott5, PG Bardy2 and RJ D’Andrea1,2,6 1 Haematology and Oncology Program, Child Health Research Institute, North Adelaide, South Australia, Australia; 2 Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia; 3 Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia; 4 Department of Genetic Medicine, University of Adelaide, Adelaide, South Australia, Australia; 5 Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia and 6 Discipline of Paediatrics and Discipline of Genetics, University of Adelaide, Adelaide, South Australia, Australia E-mail: References 1 Kaushansky K. The chronic myeloproliferative disorders and mutation of JAK2: Dameshek’s 54-year-old speculation comes of age. Best Pract Res Clin Haematol 2007; 20: 5–12. 2 Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M et al. The JAK2V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. PNAS 2006; 103: 6224–6229. 3 Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476. 4 Scott LM, Tong W, Levine M, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. NEJM 2007; 356: 459–468. 5 Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007; Epub ahead of print (June 28): 1–4. 6 Baxter E, Scott L, Campbell P, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061. 7 Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al. Proposals and rationale for revision of the World Health Organisation diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007; 110: 1092–1097. 8 Larsen TS, Christensen JH, Hasselbalch HC, Pallisgaard N. The JAK2V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. BJH 2007; 136: 745–751. Contribution of GM-CSF and IL-8 to the CD44-induced differentiation of acute monoblastic leukemia Leukemia (2008) 22, 873–876; doi:10.1038/sj.leu.2404976; published online 4 October 2007 Acute monoblastic leukemia is characterized by a monocytic differentiation blockage, resulting in the accumulation of immature monoblastic-like cells in bone marrow and circulating blood. Also designated as AML5, this acute myeloid leukemia (AML) subtype, which accounts for about 20% of adult AML cases, poorly responds to chemotherapy, and its association with hyperleukocytosis, extramedullary involvement and Leukemia Letters to the Editor 874 coagulation abnormalities contributes to its bad prognosis. AML5 blasts display high levels of the CD44 antigen, a highly glycosylated transmembrane adhesion molecule that is the main cellular receptor of hyaluronic acid. CD44 is also a signalling receptor involved in many cellular functions, including myeloid differe (...truncated)