Abstract
Somatic
mutations (
) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML).
includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic
gene inactivations (
) in CMML. We speculated that
might be associated with distinct clinicohematological features. We analyzed
in 1045 patients with MN. Of 82
cases, 66 were
, 13 were hemizygous
, and 3 were homozygous
(uniparental disomy); the remaining patients (denoted
hereafter) were either monoallelic
(n = 96) or wild-type
(n = 823). Truncation mutations were found in 83% of
vs 65% of
cases (
= .02).
hits were founder lesions in 72% of
vs 38% of
cases (
< .0001). In
, significantly concurrent hits included
(33%;
< .0001) and
/
(16%;
= .03) as compared with
When the first
hit was ancestral in
, the most common subsequent hits affected a second
, followed by
,
,
, and
patients without any monocytosis showed an absence of S
patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with
patients. Hence, while a second
hit occurred frequently,
did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally,
showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus,
might represent an auxiliary assessment tool in MN.
