• ETP-ALL, a high-risk subtype of T-ALL, is characterized by aberrant activation of the JAK/STAT signaling pathway.• The JAK1/2 inhibitor ruxolitinib demonstrates robust activity in patientderived xenograft models of ETP-ALL.Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P < .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P < .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed. (Blood. 2015;125(11):1759-1767 Introduction Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) was first described in 2009 as a subtype of T-ALL with a unique immunophenotype that includes expression of myeloid and early progenitor or stem cell markers in addition to T-cell lineage markers. 1Although overall survival for the majority of T-ALL cases has improved dramatically over the last 50 years, 2 largely due to intensification of chemotherapy regimens, many published studies suggest a large percentage of ETP-ALL cases have dismal outcomes.1,3-7 More recent studies suggest that children with ETP-ALL treated on contemporary protocols that intensify therapy based on minimal residual disease response may not fare as poorly as originally thought. 8,9 ETP-ALL, which represents ;10% to 15% of new T-ALL diagnoses in children 1,4,5 and ;10% to 30% in adults, 3,6 accounts for a disproportionate fraction of T-ALL induction failures (ie, failure to achieve a morphologic remission at the end of the first month of chemotherapy). Novel therapies with alternative mechanistic approaches are urgently needed for chemotherapy-refractory subgroups of ETP-ALL.In addition to an immunophenotype with myeloid/stem cell markers, ETP-ALL cases demonstrate a similar transcriptional and mutational landscape to myeloid leukemias and hematopoietic stem ce...

Preconception screening of consanguineous couples for recessive and X-linked disorders using genomic sequencing is practicable, and is likely to detect many more at-risk couples than any targeted panel could achieve. A couples-based approach greatly reduces the associated analysis and counselling burden.

The early progressive form of the X-linked disorder, Hunter syndrome or mucopolysaccharidosis type II (MPS II) (OMIM #309900), is characterized by cognitive decline, and pulmonary and cardiac complications that often cause death before 20 years of age. Deficiency of the lysosomal enzyme, iduronate-2-sulfatase (EC 3.1.6.13) results in deposition of the glycosaminoglycans, dermatan, and heparan sulfate in various tissues. In recent years, enzyme replacement therapy (ERT) has become the mainstay of treatment, but is expensive and ineffective in arresting cognitive decline. Hematopoietic stem cell transplantation (HSCT) also provides enzyme replacement, and may be effective in stabilizing neurocognitive function if initiated early, though data are limited. We present a case series of four patients who demonstrated neurocognitive stabilization with early HSCT. HSCT is a potentially underutilized treatment strategy for select groups of MPS II patients.