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Editorials & Perspectives EDITORIALS & PERSPECTIVES Dendritic cell, monocyte, B and NK lymphoid deficiency defines the lost lineages of a new GATA-2 dependent myelodysplastic syndrome Venetia Bigley and Matthew Collin Institute of Cellular Medicine, Newcastle University, UK. E-mail: [email protected] doi:10.3324/haematol.2011.048355 (Related Original Article on page 1221) novel immunodeficiency syndrome has recently been International Prognostic Scoring System (IPSS). defined in young adults. Known variously as dendritic It is worth emphasizing at this point that DCML deficiency cell, monocyte, B and NK lymphoid (DCML deficien - patients may have significant risk to their health before addi - A1 2 2 cy), ‘autosomal dominant and sporadic monocytopenia’ or tional cytopenias evolve. Disseminated mycobacterial infec - ‘MonoMAC’ (monocytopenia with Mycobacterium avium com - tion, PAP and carcinoma in situ may all occur prior to the onset plex), 3 it is characterized by a composite mononuclear cell defi - of an obvious myelodysplastic syndrome, underscoring the ciency, atypical mycobacterial and viral infection, and progres - fact that immunodeficiency is a cardinal feature of the disor - sion to myelodysplasia and leukemia. Strikingly, a number of der. In the series of 4 subjects described in 2011, one had mild patients also develop pulmonary alveolar proteinosis (PAP). anemia (10.3 g/dL) and one mild thrombocytopenia Patients typically present in their 3 rd or 4 th decade, although his - (123 ¥10 9/L), yet 2 required hematopoietic stem cell transplan - torical blood counts may show pre-existing monocytopenia tation (one for refractory mycobacterial infection, one for PAP) for ten years or more. A substantial number of patients devel - and a third died of influenza H1N1 prior to transplantation. 1 In op autoimmune phenomena such as erythema nodosum/pan - addition, many other factors may contribute to mild cytope - niculitis or arthritis. Solid tumors are common, notably carci - nias, including: atypical mycobacterial infection, respiratory noma in situ associated with chronic infection with human failure, autoimmune thrombocytopenia and hemolysis, and papilloma virus. Up to a third of cases have a family history drug therapy. with apparent autosomal dominant inheritance. Left untreat - The second finding from the current study is that although ed, many will die from infection, leukemia or respiratory fail - DCML deficiency can progress to a form of MDS as defined ure. Loss of dendritic cells (DCs), monocytes and B/NK lym - by standard criteria, it has some very particular and unusual phoid cells is universal, hence the term DCML deficiency to features that make it distinct from typical MDS. The main describe this syndrome. Infection with Mycobacterium avium diagnostic features are summarized in Table 1. Important complex, alluded to in the term ‘MonoMAC’, is seen in the majority of patients but not all. DCML deficiency/MonoMAC was first described by Steven Holland and colleagues at the National Institutes of Health, in Table 1. Diagnostic criteria for DCML deficiency/MonoMAC. 2 a paper published in the journal Blood in 2010. A smaller History group of subjects were also described earlier this year in a 1 report highlighting the loss of dendritic cells and specific dele - Warts and carcinoma in situ tion of bone marrow progenitor subsets. This study also Atypical mycobacterial infection demonstrated a marked increase in Flt-3 ligand and loss of reg - Respiratory failure 2 1 ulatory T cells (Tregs). As this article went to press, the genetic Family history of chest disease/leukemia basis was solved in two papers which are shortly to be pub - lished in the journal Blood. GATA-2 mutation has been found Routine tests in nearly all cases, first in a candidate gene study from the Blood count: monocytopenia 3 4 Holland group and second by exome sequencing of 4 unrelat - Lymphocyte subsets: B cell and NK cell deficiency 5 ed patients. In this issue of the journal, Calvo et al. from the Normal immunoglobulins Holland group take a more in depth look at the hematologic Bone marrow: features as bone marrow failure progresses, providing evi - megakaryocyte dysplasia (100%) dence that DCML deficiency/MonoMAC inevitably becomes normo/hypocellularity (89%) a more recognizable yet distinct form of myelodysplasia fibrosis (73%) (MDS). 3 A model of the pathogenesis of this disorder incorpo - rating these new findings is presented in Figure 1. Further investigations Through this careful description, Calvo and colleagues show Blood: clearly that advanced DCML deficiency overlaps with MDS; absolute blood DC deficiency 61%-78% of their patients had an additional cytopenia and elevated Flt-3 ligand (10-100 fold) nearly half (39%) were pancytopenic. More than half (59%) loss of peripheral Tregs also had cytogenetic abnormalities, most commonly mono - BM: somy 7/7q deletion, trisomy 8 and trisomy 1. The study sub - loss of MLP and reduction of GMP in BM CD34 + compartment jects are necessarily a more advanced group of patients than preservation of BM macrophages previously reported as the inclusion criteria were defined as CD56 + plasma cells present both a diagnosis of ‘MonoMAC’ and the development of Lungs: “additional cytopenia(s) typically associated with MDS”. The pulmonary alveolar proteinosis without GM-CSF antibodies combination of cytopenias and cytogenetics gave 15 of 18 1Associated with HPV and reduced mononuclear infiltrates; 2may be a complex of atypical patients intermediate to high scores according to the MDS infection and PAP; 3median 0.01x10 9/L compared with 0.07x10 9 in hairy cell leukemia. haematologica | 2011 96(8) 1081 Editorials and Perspectives clues are often present in patients’ case history such as a leukemic phases in which cellularity finally begins to much younger age at presentation and longstanding prob - increase and become more like typical proliferative MDS. lems with warts or poorly characterized autoimmune phe - In the description of DCML deficiency, the elevation of Flt- nomena. Atypical infection, respiratory failure, cytopenias 3 ligand was highlighted. 1 Although this has been described and family history are much stronger warnings that this is in aplastic anemia, 6 it is not a typical feature of MDS and not typical MDS. might become a useful measurement. The progenitor cell The most obvious laboratory finding is, of course, the compartment was also characterized in detail showing loss of mononuclear cells: the ‘lost lineages’ of a failing selective loss of the multi-lymphoid progenitor (MLP), a marrow that are not recognized by the standard defini - recently described pluripotent cell which appropriately tions of ‘trilineage dysplasia’. In particular, it should be gives rise to DC, monocytes and lymphoid cells. 7 easy to identify monocytopenia from the usual monocy - Granulocyte macrophage progenitors (GMP) are also tosis of sporadic MDS. It is important to note that mon - depleted but are present in sufficient numbers to sustain cytopenia may be the only deficit to be seen from auto - granulopoiesis in the early phase of the disease. All these mated counting because the loss of B cells and NK cells is observations point to the mechanism of pathogenesis being masked by preservation of peripheral T cells. DCML an intrinsic stem cell defect that preferentially affects deficiency has now earned its place in the textbook along - mononuclear cell production before progressing to global side hairy cell leukemia, as a differential diagnosis of hematopoietic failure. This mechanism has now been con - monocytopenia. Vinh et al. previously observed that the firmed by the discovery of GATA-2 mutations which are monocyte deficit is usually much more profound in likely to compromise stem cell survival and are also known DCML deficiency than hairy cell leukemia (0.01 ¥10 9/L to affect the formation of GMP, monocytes, B cells and NK compared with 0.07 ¥10 9/L). It is also vital to recognize cells in murine models of haplo-insufficiency. 8,9 that patients may present to a number of different med - The evaluation of lung disease in DCML deficiency is ical specialities, including genito-urinary medicine, infec - also very important. Mycobacterial infection may promote tious disease, respiratory medicine and rheumatology, the pathogenesis, yet also obscure the diagnosis, of under - and that failure to recognize monocytopenia in this con - lying PAP. The critical test in DCML deficiency is that GM- text is likely to result in a missed diagnosis. CSF antibodies are not detected and there is no response to Calvo and colleagues present very convincing additional administration of GM-CSF, unlike most cases of acquired diagnostic findings that separate DCML deficiency from PAP. 10 Physicians evaluating respiratory problems define the typical MDS. In most cases, megakaryocytes are dysplas - PAP of DCML deficiency as ‘secondary’ to bone marrow tic, even in the absence of thrombocytopenia, and there is failure, although this is not as straightforward as it a high rate of fibrosis (73%). Bone marrow cellularity tends appears. 11 Unexpectedly, tissue macrophages, including to be normal or low (89%), even when additional cytope - alveolar macrophages are present in normal numbers, nias have begun to evolve; it is only the very advanced despite the profound monocytopenia. 1,2 There is specula - Clinical phase asymptomatic infections infection leukemic Figure 1. Evolution of DCML carcinoma in situ trasformation deficiency/MonoMAC. PAP Schematic representation
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