DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells.

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are usually resistant to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double strand breaks (DSBs) and collapsed replication forks, rendering them dependent on DNA damage response (DDR). DNA polymerase theta (Polθ), a key element in Polθ-mediated DNA end-joining (TMEJ), is essential for survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs was diminished in DNMT3Amut leukemia cells which facilitated loading of Polθ on DNA damage and promoting TMEJ and replication fork restart. Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

Size matters: the prognostic implications of large and small deletions of the derivative 9 chromosome in chronic myeloid leukemia.

Deletions of the derivative 9 chromosome (der(9)) are associated with poor prognosis in chronic myeloid leukemia (CML). Several models have been proposed to account for this association. To distinguish between the various models we mapped the deletion in 69 Philadelphia-positive CML patients carrying a der(9) deletion and compared the size of the deletion with the patients' outcome. Our results demonstrate that patients with large deletions had a significantly worse survival than those with small deletions whereas the outcome for patients with small deletions was similar to that of patients lacking a deletion. These results support the tumor suppressor gene model for the pathogenesis of der(9) deletions, argue against alternative models and provide insight into candidate gene location.

A Polycythemia Vera Updated: Diagnosis, Pathobiology, and Treatment.

This review focuses on polycythemia vera (PV)-its diagnosis, cellular and genetic pathology, and management. In Section I, Dr. Pearson, with Drs. Messinezy and Westwood, reviews the diagnostic challenge of the investigation of patients with a raised hematocrit. The suggested approach divides patients on their red cell mass (RCM) results into those with absolute (raised RCM) and apparent (normal RCM) erythrocytosis. A standardized series of investigations is proposed for those with an absolute erythrocytosis to confirm the presence of a primary (PV) or secondary erythrocytosis, with abnormal and normal erythropoietic compartments respectively, leaving a heterogenous group, idiopathic erythrocytosis, where the cause cannot be established. Since there is no single diagnostic test for PV, its presence is confirmed following the use of updated diagnostic criteria and confirmatory marrow histology. In Section II, Dr. Green with Drs. Bench, Huntly, and Nacheva reviews the evidence from studies of X chromosome inactivation patterns that support the concept that PV results from clonal expansion of a transformed hemopoietic stem cell. Analyses of the pattern of erythroid and myeloid colony growth have demonstrated abnormal responses to several cytokines, raising the possibility of a defect in a signal transduction pathway shared by several growth factors. A number of cytogenetic and molecular approaches are now focused on defining the molecular lesion(s). In the last section, Dr. Barbui with Dr. Finazzi addresses the complications of PV, notably thrombosis, myelofibrosis and acute leukemia. Following an evaluation of published data, a management approach is proposed. All patients should undergo phlebotomy to keep the hematocrit (Hct) below 0.45, which may be all that is required in those at low thrombotic risk and with stable disease. In those at high thrombotic risk or with progressive thrombocytosis or splenomegaly, a myelosuppressive agent should be used. Hydroxyurea has a role at all ages, but (32)P or busulfan may be used in the elderly. In younger patients, interferon-alpha or anagrelide should be considered. Low-dose aspirin should be used in those with thrombotic or ischemic complications.