The C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n ‫؍‬ 6 cases). Second, a genome-wide copy-number analysis by array-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYB dup , n ‫؍‬ 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases, which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to downregulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and largescale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median, 2.2 years) and with a proliferation/ mitosis expression signature. By contrast, the MYB dup alteration was associated with the previously defined T-ALL subtypes. (Blood.

We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant CML blast crisis, particularly when lymphoid in nature.

IntroductionTransient myeloproliferative disorder (TMD) occurs in 10% to 20% of newborns with Down syndrome (DS) and usually resolves after birth. However, approximately 30% of TMD patients develop acute megakaryoblastic leukemia (AMKL) within 4 years, suggesting that TMD is a premalignant disorder and that both diseases originate in the fetus. 1-4 DS TMD and AMKL blasts harbor somatic mutations of GATA1, which encodes an essential hematopoietic transcription factor. 5-7 These mutations occur in exon 2 and result in exclusive expression of an amino-truncated protein, termed GATA-1 short (GATA-1s).Presumably, GATA-1s cooperates with trisomy 21 (T21) to induce a preleukemic state that progresses to frank malignancy through additional mutations. TMD and AMKL blasts exhibit erythro-megakaryocytic features 8-10 and GATA-1 regulates the maturation, survival, and proliferation of these lineages. 11 In contrast, little is known about how T21 itself alters hematopoiesis, particularly in the fetus, where TMD/AMKL-initiating events occur. We analyzed fetal liver hematopoiesis in T21 and control abortuses. In vitro and in vivo transplantation studies show that T21 is associated with enhanced erythroid and megakaryocytic precursor expansion, independent of GATA1 mutations. These findings provide insight into the hematopoietic abnormalities of DS and indicate how T21 might synergize with GATA-1s to promote TMD and AMKL. MethodsFetal livers were obtained from pathology specimens of week 13 to 23 abortuses. Institutional Review Board-approval was obtained from The Children's Hospital of Philadelphia and The University of Pennsylvania. Informed consent was obtained in accordance with the Declaration of Helsinki. T21 was confirmed by karyotype analysis of fetal tissue. DNA sequencing, hematopoietic assays, and gene expression analysis were performed using standard methods described in Document S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article). Approval from the Institutional Animal Care and Use Committee at the University of Pennsylvania was obtained for mouse studies. Results and discussionDS-associated TMD and AMKL initiate in utero, as evidenced clinically 1,3 and by GATA1 mutational analysis. 7,12,13 We analyzed fetal liver specimens from DS and control abortuses at 13 to 23 weeks' gestation. Histologically, T21 fetal livers were indistinguishable from controls (not shown). We isolated fetal liver hematopoietic mononuclear cells (MNCs), amplified GATA1 exon 2 by polymerase chain reaction (PCR), and subcloned the fragments. No mutations in 31 T21 or 10 control fetal liver MNC samples were detected by direct sequencing of the PCR product and 24 independent clones from each fetal liver, consistent with the relatively low incidence of GATA1 mutations (3.8%) identified by screening 585 DS newborns. 13 The absence of GATA1 mutations in our specimens allowed us to study the hematopoietic effects of T21 in isolation.We analyzed T21 and control fetal liver MNCs in methylcellulose...

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Key Points Human FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs. Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.