by Elisa Rumi, and Mario Cazzola Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms by Elisa Rumi, and Mario Cazzola Blood Volume 129(6):680-692 February 9, 2017 ©2017 by American Society of Hematology

Representative bone marrow biopsies from patients with MPNs Representative bone marrow biopsies from patients with MPNs. (A) ET: Normocellular marrow, proliferation of giant megakaryocytes with hyperlobulated nuclei, scattered or in loose clusters (hematoxylin and eosin [H&E], original magnification ×40). Representative bone marrow biopsies from patients with MPNs. (A) ET: Normocellular marrow, proliferation of giant megakaryocytes with hyperlobulated nuclei, scattered or in loose clusters (hematoxylin and eosin [H&E], original magnification ×40). (B) PV: Hypercellular marrow with erythroid proliferation and scattered pleomorphic megakaryocytes (H&E, original magnification ×20). (C) PMF: Hypercellular marrow with granulocytic proliferation and large megakaryocytes with atypical bulbous nuclei (H&E, original magnification ×40). (D) Overt PMF: Hypercellular marrow, proliferation of atypical megakaryocytes forming dense clusters, and dilated vessels with intraluminal hematopoiesis (H&E, original magnification ×40). (E) Overt PMF (collagen fibrosis): Bands of collagen fibrosis within hematopoietic lacunae (Masson trichrome staining, original magnification ×40). Courtesy of Emanuela Boveri, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692 ©2017 by American Society of Hematology

Four-generation Australian pedigree with different types of familial MPNs associated with different driver mutations. Four-generation Australian pedigree with different types of familial MPNs associated with different driver mutations. Full symbols indicate affected individuals. In this pedigree, a germ line mutation (R1569H) in the RBBP6 gene segregated with an MPN phenotype. The RBBP6 protein is a RING finger E3 ubiquitin ligase that contributes to ubiquitinate and degrade p53 in association with MDM2: mutant RBBP6 may cause an elevation in somatic mutagenesis rates through inhibition of p53 function and deregulation of cell cycle. The fact that individuals with the germ line mutation acquired somatic mutations in different genes supports the notion of genetic predisposition. Modified from Harutyunyan et al39 with permission. Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692 ©2017 by American Society of Hematology

Circulating CD34+ cells in patients with MPNs Circulating CD34+ cells in patients with MPNs. Flow cytometry enumeration of circulating CD34+ cells in patients with PV (n = 239), ET (n = 391), or PMF (n = 106). Circulating CD34+ cells in patients with MPNs. Flow cytometry enumeration of circulating CD34+ cells in patients with PV (n = 239), ET (n = 391), or PMF (n = 106). Data are shown in a box plot depicting the upper and lower adjacent values (highest and lowest horizontal line, respectively), upper and lower quartile with median value (box), and outside values (dots). Values found in PMF patients are significantly higher than those found in PV or ET patients (P < .0001): the existence of overlaps is consistent with the notion that abnormal stem cell trafficking may be found also in some patients with PV or ET, especially those with advance disease. Overall, the available evidence indicates that flow cytometry enumeration of circulating CD34+ cells represents a simple, useful tool for estimating abnormal stem cell trafficking in patients with MPNs. Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692 ©2017 by American Society of Hematology

Kaplan-Meier analysis of survival of PMF patients stratified according to their driver mutation or a clinical-molecular prognostic model that includes IPSS variables and driver mutation. Kaplan-Meier analysis of survival of PMF patients stratified according to their driver mutation or a clinical-molecular prognostic model that includes IPSS variables and driver mutation. (A) Patients stratified according to their driver mutation. This analysis illustrates the prognostic significance of the driver mutation: although all patients have a similar PMF phenotype (that is, bone marrow megakaryocytic proliferation with atypia, fibrosis grades 2/3, and abnormal stem cell trafficking), their outcome is largely determined by the driver mutant gene. (B) Patients stratified according to a clinical-molecular prognostic model. As a proof of concept, this analysis illustrates the potential of integrating clinical and molecular data for improving the prognostication precision in clinical practice and in designing clinical trials. The clinical-molecular prognostic model depicted here includes JAK2, CALR, and MPL mutation status in addition to the IPSS variables. Modified from Rumi et al85 with permission. Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692 ©2017 by American Society of Hematology

Conventional and molecular risk factors for patients with MPNs Conventional and molecular risk factors for patients with MPNs. Information is from studies discussed in the “Risk stratification” section. Conventional and molecular risk factors for patients with MPNs. Information is from studies discussed in the “Risk stratification” section. Elisa Rumi, and Mario Cazzola Blood 2017;129:680-692 ©2017 by American Society of Hematology