Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We ...studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a “myelofibrosis” phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion, or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL, or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic-phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs.
We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in ...addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (
P
< 0.001), higher WBC (
P
= 0.015), and its subsets (neutrophil, monocyte, and basophil counts), higher platelets (
P
= 0.001), lower albumin (
P
= 0.018), higher serum uric acid (
P
= 0.001), higher LDH (
P
= 0.022), and the presence of CV risk factors (
P
= 0.011). There was no significant association with driver mutations, degree of bone marrow fibrosis, PMF/SMF, or DIPSS risk categories (
P
> 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49;
P
= 0.041) and venous thrombosis (HR = 7.08;
P
= 0.030) as well as with shorter overall survival (HR 2.08;
P
= 0.009). In multivariate analyses, CKD (HR = 1.8;
P
= 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7;
P
< 0.001); its effect being more pronounced in lower (HR = 3.56;
P
= 0.036) than higher DIPSS categories (HR = 2.07;
P
= 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.
PDF
