Inactivating mutations in one of the two parental GATA2 genes lead to a reduction, i.e. a haploinsufficiency, in the cellular levels of the genes product, the GATA2 transcription factor, and thereby to a rare autosomal dominant genetic disease, GATA2 deficiency. This disease is associated with a highly variable set of disorders including the myelodysplastic syndrome, acute myeloid leukemia, and CMML. GATA2-deficiency-induced CMML, like other types of CMML, is commonly preceded by monocytosis. Diagnosis
Blood films display a range of abnormalities. A monocyte count of >1x109/L is essential for a diagnosis of CMML. Other features may include; leukocytosis (50% of cases); left shift and dysplasia of monocytes and granulocytes; presence of metamyelocytes, myelocytes and promonocytes; monocytes with hypersegmented/abnormal shaped nuclei, increased cytoplasmic basophilia and/or the presence of cytoplasmic granules; eosinophilia (in cases of CMML with eosinophilia); and spherocytosis (in cases of direct Coombs test, DCT, positive haemolytic anaemia). Platelet counts may be reduced, increased or normal. Haemoglobin levels are usually reduced with normocytic and normochromic red blood cells. Autoantibodies and cold agglutinins may be present and 10% of CMML is DCT positive.Bone marrow aspirates will display hypercellularity with increased counts of granulocytic and monocytic cells. Bone marrow core biopsies may show a predominance of myelocytic and monocytic cells, abnormal localisation of immature precursors and dysplastic megakaryocytes.
WHO criteria
The WHO criteria for diagnosis are as follows:
Persistent peripheral blood monocytosis with counts >1x109/L
No Philadelphia chromosome or BCR-ABL1 fusion gene
No rearrangement of PDGFRA or PDGFRB gene
<20% myeloblasts, monoblasts and promonocytes in peripheral blood or bone marrow
Dysplasia in one or more of the myeloid lineages; if myelodysplasia is absent or minimal then a diagnosis of CMML can be made if other requirements are met and:
A molecular genetic abnormality is present in haematopoietic cells, or
Monocytosis present for ≥3 months and other causes of monocytosis have been ruled outWHO defined CMML has two main subsets, CMML-1 and CMML-2. CMML-1 is diagnosed if myeloblasts, monoblasts and promonocytes are <5% of peripheral blood and <10% of bone marrow. CMML-2 is diagnosed if:

Myeloblasts, monoblasts or promonocytes are 5-19% in blood, or
Myeloblasts, monoblasts or promonocytes are 10-19% in bone marrow, or
Auer rods are presentCMML-1 and CMML-2 can be additionally grouped as CMML-1 or CMML-2 with eosinophilia. These are diagnosed if the above criteria are met and the blood eosinophil count is >1.5x109/L.Presence of two or more phenotypic abnormalities can aid a diagnosis of CMML in the absence of identifying cytogenetic or dysplastic features. These can include the expression of CD56 and/or CD2, or under-expression of HLA-DR.

Prognosis
Factors affecting prognosis
CMML-2 has a reduced overall survival as compared with CMML-1, with median survivals of 15 and 20 months, respectively. Myeloproliferative CMML (>13x109 monocytes/L) has a reduced survival compared with myelodysplastic CMML. A platelet count of <100 x109/L reduces overall survival. A haemoglobin level of <10g/dL has a reduced overall survival.