A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

Lipocalin-2 is associated with modulation of disease phenotype in a patient with concurrent JAK2-V617F and BCR-ABL mutation.

We investigated the role of lipocalin-2 (LCN-2) and its receptor (SLC22A17) in mediating clonal dominance in a patient with both BCR-ABL and JAK2-V617F mutations. LCN-2 mRNA showed a near 50-fold increase in expression, accompanied by down-regulation of SLC22A17, coinciding with increase in BCR-ABL transcripts, loss of JAK2-V617F and change of clinical phenotype from polycythaemia vera to chronic myeloid leukaemia. These changes were reversed after commencing imatinib mesylate. Consistent with experimental studies, BCR-ABL+ cells express LCN-2 leading to suppression of BCR-ABL- cells and explain their eventual dominance when occurring together with JAK2-V617F.

Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate.

The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.

Anaemia and iron status among blood donors in a blood transfusion unit in Malaysia.

Iron deficiency is a major complication of regular blood donation as a result of regular iron loss from each donated blood unit. Ninety-two regular blood donors and 95 first time blood donors attending a hospital-based blood transfusion centre were assessed as to their haematological and iron status by blood counts and serum ferritin levels as an indicator of iron stores. All donors had passed the haemoglobin-screening test using a copper sulphate method prior to blood donation. Ferritin levels were found to be significantly lower among regular blood donors (47.8 mmol/L) as compared to first time blood donors (94.2 mmol/L). Iron deficiency as observed by low ferritin levels was seen in 7.4% of all first time donors as compared to 17.4% in regular donors. Male first time donors showed a low prevalence of iron deficiency but the prevalence significantly increased with regular blood donation. Female first time and regular blood donors however did not show any significant differences in prevalence of iron deficiency, with both groups exhibiting prevalence rates similar to male regular donors. The association between haemoglobin levels and iron deficiency was poor and the copper sulphate-screening test was found insensitive to anaemia with many donors passing the test and donating blood despite being anaemic. It is concluded that a high prevalence of iron deficiency is present among regular male blood donors and all female donors. Besides, the use of the copper sulphate screening test as a sole criterion for anaemia screening should be reviewed. Ferritin measurements should be included in the routine assessment of blood donors especially among regular blood donors.