Should Chemotherapy Be Administered for Essential Thrombocythemia (ET) Patients with Leukemic Transformation?

Introduction: Essential Thrombocythemia (ET) is a clonal myeloproliferative disease presenting predominantly with thrombocytosis. One of its rare complications is leukemic transformation (LT). Once leukemic transformation occurs, prognosis is dismal. We aim to determine the disease profile of LT in our ET patients and evaluate if chemotherapy can alter prognosis. Methods: Clinical data of all patients diagnosed and treated with ET from 1999 to 2008 in the Department of Hematology, Singapore General Hospital, were captured in the Myeloproliferative Disease(MPD) Registry. ET patients with LT were selected. Patient characteristics, disease profile, including ET treatment, duration from ET diagnosis to LT, prior myelofibrosis (MF) history, type of chemotherapy, response and eventual survival were recorded. Results: Two hundred and thirty ET patients were diagnosed and treated from 1999 to 2008. Six patients had LT (2.6%). All were Chinese. Four were females. Age range was 47–70 years (mean 61.2 years). Transformation to acute myeloid leukemia (AML) was seen in 5 patients, after a latency period of 3–28 years. Acute biphenotypic leukemia was diagnosed in 1 patient 4 years after ET diagnosis. All patients had received hydroxyurea. There was no prior evolution to MF. Complex cytogenetics were seen in all cases. Three patients treated conservatively died within 1 month. The other 3 patients did not go into durable complete remission despite chemotherapy and succumbed within 9 months. Conclusions: Leukemic transformation in ET, though rare, is associated with grave prognosis. Outcome with chemotherapy is dismal. More studies are needed to evaluate if alternative treatment can improve survival

Delayed diagnosis of Shwachman diamond syndrome with short telomeres and a review of cases in Asia

Inherited bone marrow failure syndrome (IBMFS) including Shwachman Diamond Syndrome (SDS) can present initially to the hematologist with myelodysplastic syndrome (MDS). Accurate diagnosis affects choice of chemotherapy, donor selection, and transplant conditioning. We report a case of delayed diagnosis of SDS in a family with another child with aplastic anemia, and review reported cases of SDS in Asia. This highlights the gap in identifying inherited bone marrow failure syndromes in adults with hematologic malignancies.Published versio

A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify®

Acute myeloid leukaemia (AML) is a rapidly fatal blood cancer that is characterised by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. Methods which identify master transcriptional regulators of AML subtype-specific leukaemia cell states and their combinations could be critical for discovering novel differentiation-inducing therapies. In this proof-of-concept study, we demonstrate a novel utility of the Mogrify ® algorithm in identifying combinations of transcription factors (TFs) and drugs, which recapitulate granulocytic differentiation of the NB4 acute promyelocytic leukaemia (APL) cell line, using two different approaches. In the first approach, Connectivity Map (CMAP) analysis of these TFs and their target networks outperformed standard approaches, retrieving ATRA as the top hit. We identify dimaprit and mebendazole as a drug combination which induces myeloid differentiation. In the second approach, we show that genetic manipulation of specific Mogrify ®-identified TFs (MYC and IRF1) leads to co-operative induction of APL differentiation, as does pharmacological targeting of these TFs using currently available compounds. We also show that loss of IRF1 blunts ATRA-mediated differentiation, and that MYC represses IRF1 expression through recruitment of PML-RARα, the driver fusion oncoprotein in APL, to the IRF1 promoter. Finally, we demonstrate that these drug combinations can also induce differentiation of primary patient-derived APL cells, and highlight the potential of targeting MYC and IRF1 in high-risk APL. Thus, these results suggest that Mogrify ® could be used for drug discovery or repositioning in leukaemia differentiation therapy for other subtypes of leukaemia or cancers. </p

Galactomannan-guided preemptive vs. empirical antifungals in the persistently febrile neutropenic patient: A prospective randomized study

10.1016/j.ijid.2011.01.011International Journal of Infectious Diseases155e350-e356IJID

The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration

Rho GTPases regulate cell morphogenesis and motility under the tight control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the underlying mechanism(s) that coordinate their spatiotemporal activities, whether separately or together, remain unclear. We show that a prometastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under epidermal growth factor (EGF) stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, and cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 down-regulates local RhoA activity, which influences Rac1 binding to BPGAP1 and its subsequent activation by Vav1. Our results highlight the importance of BPGAP1 in recruiting Vav1 and Rac1 to promote Rac1 activation for cell motility. BPGAP1 also serves to control the timing of Rac1 activation with RhoA inactivation via its RhoGAP activity. BPGAP1, therefore, acts as a dual-function scaffold that recruits Vav1 to activate Rac1 while inactivating RhoA to synchronize both Rho and Rac signaling in cell motility. As epidermal growth factor receptor (EGFR), Vav1, RhoA, Rac1, and BPGAP1 are all associated with cancer metastasis, BPGAP1 could provide a crucial checkpoint for the EGFR-BPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.Published versionThis work was supported by the National Medical Research Council, a CBRG New Investigator Grant (CBRG-NIG; R-714-000-115-511 to C.Q.P.), a Journal of Cell Science—The Company of Biologists Travel Fellowship (to C.Q.P.), Cancer Research UK (C6620/A15961 to A.J.R.), and the Mechanobiology Institute of Singapore (to B.C.L.), cofunded by the National Research Foundation and the Ministry of Education, Singapore, and also supported by Ministry of Education Academic Research Fund Tier 3 (MOE Grant No: MOE2016-T3-1-002) to B.C.L