Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.
Additionally, the JAK2/STAT3 signalling pathway, which is abnormally active in CML, was inhibited by MBD2 deletion, and MBD2 deletion could up-regulate the expression of SHP1.
Key genetic aberrations include the BCR-ABL1 gene rearrangement in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and JAK2/MPL/CALR aberrations in Philadelphia chromosome-negative MPNs.
We address recent updates in the genetics and epigenetics of MPN, the mechanisms of transformation by mutant calreticulin, advances in the biology and therapy of systemic mastocytosis, clinical updates on JAK2 inhibitors and other therapeutic approaches for patients with MPNs, cardiovascular toxicity related to tyrosine kinase inhibitors and the concept of treatment-free remission for patients with CML.
Considerable effort is being made to understand the role of JAK2(V617F) at the MPN initiation and to clarify the pathogenesis and apoptosis resistance in CML, PV, ET and PMF patients.
Missense mutations of A300V, V402M, and R415H in LNK were found in 8 patients including ET (4 cases, all combined with JAK2-V617F mutation), PV (2 cases, one combined with JAK2-V617F mutation), PMF (one case, combined with JAK2-V617F mutation) and CML (one case, combined with BCR/ABL1 fusion gene).
We studied samples from 1088 persons with myeloproliferative neoplasms (MPNs) including 421 JAK2(V617F) negative subjects with ET, PMF, polycythemia vera (PV), chronic myeloid leukemia (CML) and hyper-eosinophilic syndrome (HES).
The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms, but few cases of the JAK2V617F mutation have been described in Philadelphia-positive chronic myeloid leukemia (CML) patients.
However it is not so easy, because iPSCs from hematological malignancies have been established only from myeloproliferative neoplasms including chronic myelogenous leukemia (CML) and JAK2-V617F mutation-positive polycythemia vera (PV). iPSC technology has great potential to promote oncology research based on patient samples.
Previous studies have reported FLT3 mutation in as many as 9.2% of myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), as well as in chronic myelogenous leukemia, that are negative for the JAK2V617F gene mutation; no FLT3 mutation has been found in JAK2-positive MPNs, suggesting that the mutations are mutually exclusive.
The present report describes two chronic myelogenous leukemia (CML) patients with the JAK2-V617F mutation who were in complete hematologic and cytogenetic remission and subsequently developed clinical features of essential thrombocythemia under treatment with tyrosine kinase inhibitors.
LCN-2 mRNA showed a near 50-fold increase in expression, accompanied by down-regulation of SLC22A17, coinciding with increase in BCR-ABL transcripts, loss of JAK2-V617F and change of clinical phenotype from polycythaemia vera to chronic myeloid leukaemia.
In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV.
We recently demonstrated that the AHI-1 oncogene physically interacts with BCR-ABL and JAK2 and mediates cellular resistance to TKI in CML stem/progenitor cells.
Chronic myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells, which fall into distinct categories based on a number of characteristics including the presence of the BCR-ABL1 gene fusion (chronic myelogenous leukemia) or the JAK2(V617F) mutation (polycythemia vera, primary myelofibrosis, and essential thrombocythemia).
Abnormalities of tyrosine kinase proteins are well recognised in myeloid malignancies, mutation in the cytoplasmic tyrosine kinase JAK2 (V617F) is key in the pathogenesis of myeloproliferative neoplasms, and translocations involving ABL key in the development of chronic myeloid leukaemia.