In 5 V617F+ patients who progressed to AML, we show that SNP-A can allow for the detection of two modes of transformation: leukemic blasts evolving from either a wild-type jak2 precursor carrying other acquired chromosomal defects, or from a V617F+ mutant progenitor characterized by UPD9p.
We previously showed that CD34⁺/CD38⁻ acute myelogenous leukemia (AML) cells, which contain leukemia stem cells, expressed a greater amount of the phosphorylated forms of JAK2 and STAT5 (p-JAK2 and p-STAT5) than their CD34⁺/CD38⁺ counterparts.
Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described.
JAK2(V617F) was identified in patients previously diagnosed with a myeloproliferative disorder or acute myeloid leukemia transformed from myeloproliferative disorder, whereas a wild-type genotype was identified in patients with reactive conditions or de novo acute myeloid leukemia.
We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene.
We hypothesized that the JAK2V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling.
In the test of blind screening of 223 samples (111 Ph- MPNs, 60 Ph+ chronic myeloid leukemia, and 52 acute myeloid leukemia), JAK2V617F mutations were found in 78 (70%) patients with MPNs, but in none with chronic and acute myeloid leukemia.
JAK2 variants were detected at a higher frequency in the MPN>AML cohort (15.3%) in comparison with the MPN (4.6%; P < .001) and AML cohorts (5.2%; P < .001).
The 20-yr lag phase between the polycythemia vera and the AML adds indirect evidence to the growing realization that the leukemic transformation in patients with MPN occurs from in a JAK2 wild-type stem cell.
We conclude that JAK2-V617F-positive MPD frequently yields JAK2-V617F-negative AML, and transformation of a common JAK2-V617F-negative ancestor represents a possible mechanism.
This study highlights the therapeutic potential of JAK2/HDAC dual inhibitors in treating AML and IFIs and provides an efficient strategy for multitargeting drug discovery.
Additionally, <b>18e</b> showed an excellent bioavailability (<i>F</i> = 58%), a suitable half-life time (<i>T</i><sub>1/2</sub> = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that <b>18e</b> might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.
Six genes (AKT1, RUNX1, LTB, SDC1, RUNX1T1, and JAK2) from the imbalanced regions have been reported to be involved in AML, whereas other 30 cancer genes, not previously reported in an AML context, were identified as imbalanced.
Here we review results of recent studies with first-generation JAK2 inhibitors in the treatment of MPN and second-generation ABL and Flt3 inhibitors in CML and AML, respectively.
Because of the low incidence of JAK2 mutation in acute myeloid leukemia (AML), the clinical features of AML with JAK2 mutation are rarely reported so far, either transformed from essential thrombocythemia (ET) or de novo AML.
JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes.
As the abnormal activation of JAK2 associated pathway is important to AML, we try to explore the effect of HHT on JAK2-STAT pathway in AML cells, thus supplying theoretical basis for wider use of HHT.
ASXL1 and TET2 showed similar mutation frequencies across all analyzed entities while RUNX1, CBL, and JAK2 were specifically mutated in patients with acute myeloid leukemia (AML), chronic myelomonocytic leukemia, and myeloproliferative neoplasms, respectively.
FLT3 and JAK2 Mutations in Acute Myeloid Leukemia Promote Interchromosomal Homologous Recombination and the Potential for Copy Neutral Loss of Heterozygosity.
Chr12 abnormalities did not significantly correlate with JAK2 status, progression to acute myeloid leukemia, or survival, however patients with 12q24 abnormalities trended toward poorer outcomes.