A family inheriting different subtypes of acute myelogenous leukemia

Abstract

Rare inherited cancer syndromes have proven invaluable for the identification of genes involved in the more frequent corresponding noninherited cases. We report on a family with an adult onset, incompletely penetrant, autosomal dominant syndrome of myelodysplasia and acute myelogenous leukemia, affecting at least eight, and probably ten, individuals from three generations. The patients have developed leukemias differing in morphologic subtype, tumor cytogenetics, and abruptness of presentation. Some have presented with acute onset and others with protracted myelodysplasia. This family does not have an unusual incidence of other malignancies; however, one person at 50% risk of inheriting this gene developed atypical mycobacterium infection in the absence of leukemia, but also without appreciable risk factors for acquired deficiencies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in the bone marrow of red cell and platelet maturation defects. A search for mutations in diseased marrows fails to detect abnormalities of p53 or N-ras. Two of the affected family members, third degree relatives, have co-inherited a constitutional chromosomal banding variation of 9p21-22, potentially suggesting linkage to this locus. The variable penetrance and expressivity of this syndrome support a multistep model of leukemia evolution, in which the gene defined by this family's syndrome is the signal step.

GATA factor mutations in hematologic disease

“…96,101 Bone marrow histopathological changes can be subtle, not always present before onset of overt bone marrow failure, and characteristically include hypolobated micromegakaryocytes, large osteoclastlike megakaryocytes, dyserythropoiesis (consisting of nuclear budding, binucleation, and megaloblastoid changes), and myeloid dysplasia (as evidenced by maturation asynchrony and hypogranularity). 88,102,103 Hypocellularity can also be observed. In accord with peripheral cytopenias, flow cytometric analysis of bone marrow from patients with GATA2 deficiency reveals significant reductions in monocytes, B cells, and NK cells.…”

GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity

“…23 Atypical megakaryocytes were identified in 92% of patients, even in those without overt MDS ( Figure 3B-D). 23,24 Forty-eight percent had abnormal bone marrow cytogenetics, including trisomy 8 in 24% and monosomy 7 in 16%. There were 14% of patients whose condition evolved into AML, and 8% met criteria for CMML.…”

The evolution of cellular deficiency in GATA2 mutation

“…13 Some historical cases of familial AML are now also known to be due to GATA2 mutation. [14][15][16] It is unknown whether failure of mononuclear cell development is a consequence of GATA2 mutation in all patient groups. In particular, hereditary AML may arise without a preceding "accessory" hematopoietic phenotype.…”