Induction of Truncating ASXL1 Mutations in Human CD34+ HSPCs Mimics Human ASXL1-Mutated Clonal Hematopoiesis and Progression to Myeloid Malignancies

Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations.

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1–BAP1 complex

ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a...

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation.

Inherited or sporadic heterozygous mutations in the transcription factor GATA2 lead to a clinical syndrome characterized by non-tuberculous mycobacterial and other opportunistic infections, a severe deficiency in monocytes, B cells and natural killer cells, and progression from a hypocellular myelodysplastic syndrome to myeloid leukemias. To identify acquired somatic mutations associated with m...

Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10-30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly,...

Mutations of ASXL1 and TET2 in aplastic anemia.

Acquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome. The late evolution to myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) is the most common clonal complication in refractory patients and in those who do not achieve a robust response. The reported rates of clonal evolution varied i...