Understanding ROR1

ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.

Click HERE: https://www.youtube.com/watch?v=Zji6Fux_WGo

Thanks to Patient Power!fig1

 

Our New Newsletter is HOT off the Press!

We have our new newsletter is available!!  New news and articles letting you know the latest news in regards to CLL and the Blood Cancer Research Fund. Special thanks to Carolina Bump for her tireless efforts to get this information together!

Click here: Insight – BCRF Winter 2013 Newsletter 

Removing the Block and ABT199

 

By Michael Choi, M.D. 

Chronic Lymphocytic Leukemia (CLL) has been described as a relentless accumulation of leukemic cells due to an imbalance of excessive cell proliferation and defective cell death. In other words, CLL cells have both “pro-survival” and “anti-death” mechanisms. In a previous article, we described the pathways on the pro-survival side, such as the B-cell receptor associated tyrosine kinases, and clinical trials of agents that block those pathways. In this article, we will focus on the opposite side of the equation: the mechanism by which CLL cells escape cell death, and how new therapies can overcome it.

Cell death is normally tightly regulated by proteins in the B-cell lymphoma/ leukemia 2 (BCL-2) family. BCL-2 sequesters and disables the proteins BAX and BAK, which when left free of BCL-2, signal a cell to die. When normal cells or their DNA are damaged, BCL-2 is bound and occupied by other signals, thus freeing BAX and BAK to trigger cell death. CLL cells (and other cancerous cells) have extremely high levels of BCL-2, to the point that its grasp on BAX and BAK cannot be overcome.

In recent years, therapies that inhibit BCL-2 have been designed and largely pioneered by our group and collaborators in the CLL Research Consortium. The pharmaceutical company Abbott has developed and refined drugs that inhibit BCL-2, including ABT-737, ABT-263, and ABT-199. In a phase 1 study treating patients with relapsed CLL, ABT-263 was strikingly effective: 90% of patients experienced a significant decrease in lymphocyte counts and the median progression-free interval was over 2 years. (Roberts, Seymour, Brown, Wierda, Kipps, et al. JCO, 2011)

Although very well tolerated overall, the most common adverse effect of ABT- 263 was a decrease in platelet counts due to the inhibition of one particular BCL-2 family member that is important for platelet function. Due to this, ABT-199 was developed to avoid this effect on platelets. Trials of this oral drug are ongoing, both alone and combined with other agents. Although these are early phase studies (phase 1 and 2), our years of experience with Abbott compounds and the clinical proof that blocking BCL-2 is an effective treatment make us confident that these new agents will represent a significant step towards our goal of curing this disease.

MicroRNAs in Chronic Lymphocytic Leukemia

 By Dr. Marek Mraz 

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the Western world and remains an “enigma” in modern hematology. The B-cell receptor (BCR) signaling pathway of CLL cells is known to affect the pathogenesis of CLL. The BCR signaling pathway is a complex network of proteins that regulate the response of normal and malignant B cells to the stimulation of the BCR by antigens. Morever, some of the prognostic markers used today in the treatment of CLL, such as ZAP-70 and mutation status of the immunoglobulin heavy chain gene (IGVH), are involved in BCR signaling pathways. A key research question, then, is what regulates the BCR in CLL cells? What makes a CLL cell so receptive to BCR stimulation?

Interestingly, a recently discovered group of molecules called MicroRNAs (miRNAs) was found to affect the BCR signaling pathway. MiRNAs are small sequences of RNA (one of the two types of nucleic acids present in the cells), which do not encode for proteins, but rather work to regulate the expression of other genes (see graphic). MiRNAs have been found to be uniquely expressed in almost all types of human cancers and are key players in the development of tumors. They also belong to a larger family of RNAs, called non-coding RNAs, whose expression is also deregulated in cancer.

Dr. Marek Mraz’s previous work described aberrant expression of miRNAs in the most aggressive CLL subtype (p53 aberration), and found that microRNA expression was associated with immunoglobulin structure. Presently, Dr. Mraz is investigating the role that a specifc miRNA, called miR-150, plays in the regulation of BCR signaling pathways in CLL. As part of this project, he is performing a large-scale search for the proteins regulated by this molecule. His results suggest that this miRNA might contribute to the deregulation of BCR signaling of CLL cells and thus contributes to their aggressive and cancerous behavior. The novel data on this miRNA’s contribution to BCR signaling in CLL will be presented at the American Society of Hematology (ASH) Annual Meting in December 2012. More importantly, Dr. Mraz’s work and research identifying relevant miRNAs, will ultimately be used to develop miRNA-based therapeutics.

Trisomy 12 and NOTCH1 Mutations

Trisomy 12 CLLs progress through NOTCH1 mutations

B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western societies.1 CLL cases can be subgrouped into two types, aggressive or indolent, defined as cases that express high levels of Zeta-chain-associated protein kinase 70 (ZAP70) and unmutated immunoglobulin heavy-chain variable-region genes (IGHV), or low to negligible ZAP70 and mutated IGHV. Chromosomal aberrations can be identified in more than 80% of patients.1 The most frequent genetic alterations include deletion/inactivation of 13q14 (>50%), deletion of 11q22–23 (18%), trisomy of 12 (12–16%) and deletion 17p (7–10%).1

Trisomy 12 identified using Fluorescent In Situ Hybridization (FISH)

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