Juvenile myelomonocytic leukaemia: the quest for more specific therapies
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1 4 Juvenile myelomonocytic leukaemia: the quest for more specific therapies H. Helsmoortel, MSc 1,2, T. Lammens, PhD 1, N. Van Roy, PhD 2, J. Philippé, MD, PhD 3, P. De Paepe, MD, PhD 4, Y. Benoit, MD, PhD 1, F. Speleman, PhD 2, P. Van Vlierberghe, PhD 2, B. De Moerloose, MD, PhD 1 Juvenile myelomonocytic leukaemia is a very rare, aggressive stem cell disorder predominantly affecting infants and young children. Current survival rates are disappointing and the only available curative therapy is haematopoietic stem cell transplantation. Over the last years, intensive research efforts elucidated a plethora of molecular aberrations involved in the pathogenesis of juvenile myelomonocytic leukaemia. Current investigations are mainly directed towards the complete unravelling of the molecular biology behind the disease in order to find more specific drugs. This review will focus on the diagnosis, genomic characterisation and the use of experimental therapies in juvenile myelomonocytic leukaemia. (Belg J Hematol 2014;5(4):119-24) Introduction Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood, characterised by an overproduction of monocytic cells. 1 JMML was previously referred to as juvenile chronic myeloid leukaemia (jcml), chronic myelomonocytic leukaemia of infancy (CMMoI) or infantile monosomy 7 syndrome. It is a clonal stem cell disorder classified by the World Health Organisation (WHO) as a combined myeloproliferative/myelodysplastic disease because of an overproduction of (mature and immature) granulocytic and monocytic cells, while erythropoiesis and thrombopoiesis are decreased. Indeed, patients with JMML frequently display anaemia and thrombocytopenia (Figure 1). In its terminal stage, the disease may progress to acute myeloid leukaemia (AML). 2 Epidemiology, clinical picture, diagnostic work-up and treatment JMML is an extremely rare disease, with an incidence varying from 0.6 to 1.2 per million children (0-14 years) per year in different studies. 3,4 Since 1998, the European Working Group on MDS and JMML (EWOG-MDS) registers all JMML patients in seventeen European countries, including Belgium. This centralised database is a welcome tool for epidemiologic studies, as well as for clinical and molecular research. The median age at diagnosis is two years. Initially, patients present with various non-specific symptoms that could also be associated with a bacterial or viral infection. Fever, coughing, splenomegaly and skin infiltration are frequently found. Juvenile xanthogranuloma occurs in some patients as well. Appropriate laboratory 1 Department of Paediatric Haematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium, 2 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 3 Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium, 4 Pathological Anatomy, AZ Sint Jan Bruges, Bruges, Belgium. Please send all correspondence to: H. Helsmoortel, MSc, Centre for Medical Genetics Ghent (CMGG), Department of Paediatric Haematology- Oncology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium, tel: , hetty.helsmoortel@ugent.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: diagnosis, experimental therapy, juvenile myelomonocytic leukaemia, molecular aberrations, paediatric, Ras signalling. Acknowledgements: The Ghent JMML research group is supported by the Kinderkankerfonds and by grants of the Foundation against Cancer ( ) and of the King Baudouin Foundation (2013-J ). P. Van Vlierberghe is a postdoctoral fellow of the Research Foundation Flanders and the recipient of an Odysseus type two research grant. 119
2 Figure 1. Juvenile myelomonocytic leukaemia is characterised by an overproduction of granulocytic and monocytic cells, anaemia and thrombocytopenia. tests should exclude infections since JMML might mimic an infection with Epstein-Barr virus, cytomegalovirus, human herpes virus 6 and others. 5-7 A blood examination usually shows high white blood cell counts, anaemia, thrombocytopenia, monocytosis and an elevated haemoglobin F level for age. The diagnostic criteria of JMML are presented in Table 1. JMML is diagnosed if all criteria listed in column A are met, plus at least one parameter of column B or at least two parameters of column C. The percentage of blasts in peripheral blood and bone marrow is lower than 20% and myeloid precursors are found in blood smears. It is usually easier to diagnose JMML by morphologic examination of blood smears than bone marrow smears. Bone marrow examinations are used to distinguish JMML from acute myelomonocytic leukaemia (AML-M4), which has a blast percentage of 20% or higher. In JMML, the bone marrow is hypercellular with granulocytic proliferation and less monocytes as compared to the peripheral blood. 8 The BCR/ABL fusion gene and corresponding Philadelphia chromosome should always be absent. Monosomy of chromosome 7 is the most frequent karyotypic abnormality, seen in 25% of JMML patients. At the genetic level, more than 85% of the patients have a mutation in KRAS, NRAS, PTPN11, NF1 or c-cbl causing aberrant activation of the Ras signalling pathway. Due to the mutations in the Ras pathway, JMML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF) in vitro. JMML can be associated with the congenital disorder neurofibromatosis type I, which is caused by germline mutations in the neurofibromin gene (NF1). 9 JMML is also seen in association with Noonan syndrome, which is caused in half of the cases by a germline mutation in exon 3 of PTPN11. Leukaemia diagnosed in Noonan children shows a milder course and can spontaneously regress. 10 Notably, JMML patients without Noonan syndrome are sometimes characterised by a different somatic mutation affecting PTPN11 but never show spontaneous regression. The survival of most patients is dismal and haematopoietic stem cell transplantation (HSCT), either with matched related or unrelated donor bone marrow, peripheral blood stem cells or cord blood, is considered the only standard of care. 11 This very invasive treatment modality is associated with severe side effects and only provides an event-free survival of about 50%. 12 Recent evidence suggests that the outcome of HSCT 120
3 4 Table 1. Diagnostic criteria. A. All of the following B. One parameter sufficient C. Two parameters if no parameter B present Monocytes > 10 9 /µl Mutations in RAS, PTPN11, NF1 or c-cbl WBC > 10 x 10 9 /µl < 20% blasts in PB/BM Monosomy 7 Circulating myeloid precursors Absence of BCR/ABL fusion gene NF1 diagnosed Clonal abnormality besides monosomy 7 Splenomegaly Increased HbF for age GM-CSF hypersensitivity PB Peripheral blood; BM Bone marrow; NF1 Neurofibromatosis type 1; WBC White blood cell count; HbF Haemoglobin F; GM-CSF Granulocyte-macrophage colony stimulating factor. depends partially on the molecular aberrations. Patients with mutations in NF1, somatic PTPN11, and somatic KRAS and without any known mutations have no chance of survival without HSCT. Patients with germline CBL and germline PTPN11 mutations however show no difference in survival with or without HSCT. 13 Cytoreduction with 6-mercaptopurine may be an equally effective therapy, and close clinical observation should guide the therapeutic decision. Finally, some, but not all, patients with somatic NRAS mutations survive without HSCT. Here the severity of the disease should be the decisive factor. In contrast to the significant clinical improvements that have been achieved in other childhood cancers over the last decade, it seems that the survival of JMML patients has reached a plateau level. Further elucidating the prognostic significance of the molecular markers will guide decisions on necessity and timing of HSCT. On the other hand, unravelling the molecular networks involved in JMML and identifying molecular targets for new therapeutics might result in alternatives for HSCT. The molecular characterisation of JMML Over the last years, molecular research in JMML has mainly focused on the characterisation of novel genetic lesions at the DNA level. Multiple gross chromosomal abnormalities have been documented in JMML patients, with monosomy of chromosome 7 being the most important one. 14 RAS mutations Mutual exclusive mutations in NRAS, KRAS, PTPN11, c-cbl or NF1 leading to a hyperactive Ras signalling pathway are found in 85% of JMML patients (Figure 2). Ras family members have an active GTP-bound state and an inactive GDP-bound state. Guanine nucleotide exchange factors (GNEFs) accelerate the change between the passive and the active conformation, whereas GTPase activating proteins (GAPs) have an opposite effect. Gain of function mutations in GNEFs and loss of function of GAPs are frequently oncogenic. NRAS and KRAS proteins are crucial early mediators in the signalling cascade. Somatic activating point mutations are found in 25% of JMML patients. These are located in exons 12 and 13 of NRAS and exon 13 of KRAS. 15 PTPN11 encodes the tyrosine phosphatase protein Shp2 that dephosphorylates its downstream targets and thereby activates GNEFs and Ras signalling. Mutations in PTPN11 result in a constitutively active protein and thus an overactive Ras pathway. Half of the patients diagnosed with Noonan syndrome have a germline mutation in PTPN11 and frequently display myeloproliferative features. Somatic mutations in non-syndromic de novo JMML patients (without Noonan syndrome) appear in 35% of the cases and affect different base substitutions in the same exons. 16,17 This led to the hypothesis that germline mutations associated with Noonan syndrome are weaker concerning their transforming ability and can therefore be tolerated during development. 1 Neurofibromin is a tumour suppressor protein encoded by the NF1 gene and stimulates the hydrolysis from the active GTP-Ras into inactive GDP-Ras. Loss-of-function mutations in this GAP cause an increase in active Ras protein. Patients diagnosed with neurofibromatosis type I (NF1), caused by a germline NF1 mutation, have a 121
4 Figure 2. Overview of the frequently mutated genes in juvenile myelomonocytic leukaemia. GAP GTPase activating protein; GNEF Guanine nucleotide exchange factor; GM-CSF Granulocyte-macrophage colony stimulating factor; F Farnesyl to 500-fold increased risk in developing myeloid malignancies, especially JMML, which is associated with the loss of the remaining NF1 wild type allele. 9 About 11% of JMML patients show clinical signs of NF1. 11 Notably, somatic NF1 mutations have also been identified in JMML patients without clinical signs of NF1. Similar somatic mutations in NF1 have also been found in children with acute myeloid leukaemia (AML) and T-cell acute lymphoblastic leukaemia (T-ALL). 18 More recently, homozygous mutations in the casitas B-lineage lymphoma gene (c-cbl) were detected in 10 to 15% of JMML patients. 19 Loss of function of this tumour suppressor leads to increased amounts of activated receptor tyrosine kinases and an impaired binding to Grb2, eventually leading to activated Ras signalling (Figure 2). Bi-allelic inactivation in JMML often arises from acquired uniparental copy-neutral loss-of heterozygosity of c-cbl. 20 Other pathways The JAK2 gene, a key player in the JAK-STAT pathway, is frequently mutated in chronic myelomonocytic leukaemia and was examined in JMML as well. However, research efforts directed towards finding similar mutations in JMML remained unsuccessful. 21 A subset of JMML samples showed aberrant phosphorylation of Stat5, which was correlated with outcome. 22 Moreover, sporadic mutations in ASXL1 and FLT3 were found in JMML patients. 23 Epigenetics and gene expression Methylation studies identified two phenotypic variants of JMML characterised by different methylation patterns that are independent from mutational status. Patients with a hypermethylated phenotype are associated with a significantly worse outcome. Differentially methylated genes include BMP4, CALCA, CDKN2B, RARB, RASSF1A and PTEN. 24 Hypermethylation of the promoter region of PTEN is an interesting feature since this tumour suppressor gene acts downstream of Ras (through PI3K and AKT) to counteract the positive growth signals coming from an overactive Ras. Lower amounts of PTEN mrna and protein were found in a considerable amount of JMML patients supporting the hypothesis that hypermethylated PTEN is unable to produce sufficient negative growth signals in JMML patients. 25 Finally, gene expression profiles can segregate JMML patients into two groups, based on AML-like and non- AML-like gene expression signatures, with the latter ones having a significantly better prognosis. 26 Targeted therapy and experimental treatment modalities Chemotherapy prior to HSCT with 6-mercaptopurine, 122
5 4 Key messages for clinical practice 1. JMML is a rare disease, affecting (very) young children. 2. Diagnosis is difficult and the application of diagnostic criteria (provided by EWOG-MDS) is recommended. 3. The only current therapy is haematopoietic stem cell transplantation, with only a 50% success rate. 4. Hyperactive Ras signalling is a hallmark of JMML due to mutations in NRAS, KRAS, PTPN11, c-cbl or NF1. 5. Experimental therapies based on molecular knowledge are awaiting implementation in clinical practice. cytarabine or intensive AML induction courses yielded variable and unsatisfactory results. 1 Since hyperactive Ras is the hallmark of JMML, inhibition of Ras signalling emerged as a promising hit for targeted therapy. However, most Ras inhibitors have non-specific effects and also target Ras in non-malignant cells hampering the translation of these compounds to the clinic. Upstream Ras inhibitors, such as farnesyl transferase inhibitors, have also been studied extensively in JMML. These compounds prevent the farnesylation of Ras, which is necessary to translocate Ras proteins to the plasma membrane, but also showed limited success. Probably cells circumvent the inhibitor by geranylation of Ras (adding of a geranyl group) instead of farnesylation, both having a similar effect. 1 Moreover, the development of a specific inhibitor for Shp2 (PTPN11) is difficult since its catalytic site shows high homology with that of Shp1. Attempts are being made to find a specific inhibitor, but these have not been tested in the context of JMML. Inhibition of GM-CSF with E21R reduced the number of JMML cells in xenografted mice and seemed to preferentially eliminate leukemic cells. 27 Targeting downstream pathways seemed to be more effective as illustrated by the recent results on Raf1 inhibition. Raf1 functions immediately downstream of Ras and can be inhibited by a DNA enzyme that cleaves the RAF1 mrna. This so-called Raf-1 enzyme reduced colony formation of JMML cells and had no effect on normal bone marrow cells, an important characteristic for potential cancer therapeutics. Immunodeficient mice engrafted with JMML cells that were treated with this enzyme showed remarkable reduction of tumour cells in their bone marrow. 28 Phase II clinical trials have now been planned with another Raf1 inhibitor, sorafenib. 2 Another molecule downstream of Ras is Mek. The Mek inhibitor CI-1040 prevents activation of Erk1/2, but yielded minor responses in murine models mimicking JMML. Recently, Chang et al. demonstrated that another Mek inhibitor, PD , is able to improve a JMMLlike disease in Nf1 -/- knockout mice. 29 Inhibition of mtor (involved in the PI3K/Akt/mTOR pathway) with rapamycin also showed antileukemic activity in JMML patients. 1 Researchers also tried to block angiogenesis in murine myeloid leukaemia models. Combination therapy with the angiogenic inhibitors endostatin and PI-88 reduced the number of JMML cells in engrafted mice by about 95% without affecting normal bone marrow cells. 30 Finally, treatment with the DNA hypomethylating agent azacytidine in a JMML patient with monosomy 7 and KRAS mutation whose parents refused HSCT, resulted in complete remission. 31 This interesting observation led to a phase II study evaluating azacytidine in children with JMML and MDS, which is currently open in the EWOG-MDS and Innovative Therapies for Children with Cancer (ITCC) consortium as trial ITCC-015/Nederlands Trial Register NTR2578. Conclusion Over the past years tremendous progress has been made in characterising the molecular aberrations in JMML. This led to diagnostic improvement, since 85% of the children harbour a mutation in NRAS, KRAS, PTPN11, NF1 or c-cbl. Further research is now being conducted to elucidate the cause of JMML development in the remaining 15% of patients. Most molecular aberrations identified in JMML lead to hyperactive Ras signalling, but recent studies have also implicated other pathways and epigenetic deregulations 123
6 in the biology of this disease. Unfortunately, this increased knowledge has not translated into the use of targeted therapies in clinical practice yet. Continued research efforts combining genomic, transcriptomic, epigenetic and proteomic approaches will be necessary to develop specific antileukemic drugs. References 1. Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol. 2011;152(6): Chan RJ, Cooper TT, Kratz CPC, et al. Juvenile myelomonocytic leukaemia: a report from the 2nd International JMML Symposium. Leuk Res. 2009;33(3): Passmore SJ, Chessells JM, Kempski H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a populationbased study of incidence and survival. Br J Haematol. 2003;121(5): Hasle H, Wadsworth LD, Massing BG, et al. A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada. 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Myeloproliferative disorder in Noonan syndrome. J Pediatr Hematol Oncol. 2011;33(1):e Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 1997;89(10): Locatelli F, Nöllke P, Zecca M, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood. 2005;105(1): Conference E-MC. Guidelines for Hematopoietic Stem Cell Transplantation (HSCT) in Childhood MDS and JMML. [Internet] [cited 2013 Sep 30]. Available from: Hasle H, Arico M, Basso G, et al. Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia. 1999;13(3): Flotho C, Valcamonica S, Mach-Pascual S, et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia. 1999;13(1): Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34(2): Kratz CP, Niemeyer CM, Castleberry RP, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/ myeloproliferative disease. Blood. 2005;106(6): Balgobind BV, Van Vlierberghe P, van den Ouweland AM, et al. Leukemiaassociated NF1 inactivation in patients with paediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood. 2008;111(8): Loh ML, Sakai DS, Flotho C, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114(9): Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9): Pérez B, Kosmider O, Cassinat B, et al. Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. Br J Haematol. 2010;151(5): Kotecha N, Flores NJ, Irish JM, et al. Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell. 2008;14(4): Gratias EJ, Liu YL, Meleth S, et al. Activating FLT3 mutations are rare in children with juvenile myelomonocytic leukemia. Pediatr Blood Cancer. 2005;44(2): Olk-Batz C, Poetsch AR, Nöllke P, et al. Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood. 2011;117(18): Liu YL, Castleberry RP, Emanuel PD. PTEN deficiency is a common defect in juvenile myelomonocytic leukemia. Leuk Res. 2009;33(5): Bresolin S, Zecca M, Flotho C, et al. Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol. 2010;28(11): Iversen PO, Lewis ID, Turczynowicz S, et al. Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice. Blood. 1997;90(12): Iversen PO, Emanuel PD, Sioud M. Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth. Blood. 2002;99(11): Chang T, Krisman K, Theobald EH, et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013;123(1): Iversen PO, Sorensen DR, Benestad HB. Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia. 2002;16(3): Furlan I, Batz C, Flotho C, et al. Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7. Blood. 2009;113(12):
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