Myeloproliferative neoplasms (MPNs) are a type of chronic cancer of the bone marrow/blood that can become worse over time, especially if left untreated. The major MPN subtypes are primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET).
MPNs are characterized by myeloproliferation- uncontrolled growth of the blood stem cells in the bone marrow and increase of one or more of the three blood cell types in circulation, namely red and white blood cells, and platelets,- specific morphologic features (i.e., appearance) in the bone marrow, such as fibrosis (scarring of the bone marrow), hypercellularity (presence of excess cells in the bone marrow); and certain genetic mutations (abnormalities in specific genes present in malignant cells) among others.
The three classic MPNs present different clinical phenotypes (observable characteristics) and a range of morphologic/molecular features. Primary MF (PMF) is characterized by bone marrow fibrosis (bone marrow is progressively replaced with fibers, a process that progressively leads to cytopenias (low counts of the three main blood cell types) and ultimately failure of the marrow to produce blood. MF is the most aggressive MPN whereas PV and ET constitute the more indolent subtypes. MF can occur as the primary problem- PMF- or evolve from PV or ET to the fibrotic phase (secondary MF). PV patients typically have an elevated hematocrit and harbor the JAK2 V617F mutation. ET is the most indolent MPN and is characterized by a high number of platelets (cells that control bleeding).
"Driver" Mutations in MPN
In 2005, the landmark discovery of the JAK2 V617F mutation and its involvement in MPN biology was reported. The JAK2 mutation is nearly ubiquitous in PV patients (95%), and is detected in about 50-60% of PMF or ET patients. CALR is another mutation detected in the bone marrow/blood cells of MF and ET patients (25-30% in MF, and 20-25% in ET). In addition, a gene called MPL is mutated in 10-20% of ET and MF patients. These three mutations in the genes JAK2, CALR and MPL typically are mutually exclusive; they are called “driver” mutations because they activate signaling that makes affected cells grow without control (this is called the JAK-STAT pathway inside the bone marrow/blood cells). Notwithstanding the fact that JAK2, CALR and MPL are not the cause of MPN, clinical and experimental findings clearly support the critical impact of these mutations in the manifestation of a specific MPN phenotype.
MPN Transformation to Acute Myeloid Leukemia (AML)
MPNs can transform to AML in 20-25% of the cases. AML is a disease where “baby” bone marrow cells called blasts start to grow without control (comprising more than 20% of the bone marrow cells) and do not go through the maturation process. A few “non-driver” mutations (mutations in genes that are not directly related to activation of the JAK-STAT pathway) or “triple-negative” status for the three driver mutations (no JAK2, CALR, and MPL) may play a role in transformation of MF to AML. For example, IDH1 and IDH2 mutations are detected in about 20% of the patients with MPN in transformation to AML. Bone marrow biopsies, molecular studies (determination of specific mutations in the bone marrow/blood cells), and cytogenetic testing (morphology of chromosomes) are important for diagnostic and prognostic assessment; and evaluation of response to treatment and progression to AML.
MPN Tissue Bank at MD Anderson
A unique aspect of our MPN research program is the establishment of the largest central MPN tissue bank and the corresponding clinical database worldwide. Our MPN tissue bank comprises specimens and clinical data (including bone marrow biopsies and mutations) for more than 2,500 patients. Retrospective studies of bone marrow specimens and blood samples from MPN patients are crucial in assessing new medications. Specimens collected before and during treatment can be used to understand prognosis and response to treatment. In addition, our tissue bank is used to conduct translational research studies and explore the pathophysiology of MPN; and, in certain cases, the underlying mechanism of transformation to AML.