Leukemia Essay

Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. AML is a heterogeneous disease which results from genetic alterations in normal hematopoietic stem cells. These alterations induce differentiation arrest and/or excessive proliferation of abnormal leukemic cells or blasts [1]. Recent genomic studies have identified that recurrent somatic mutations in patients with AML blocks differentiation and/or enhance self-renewal by altered transcription factors [2,3]. The genetic or the epigenetic changes acquired by AML cells disrupt the key growth regulatory pathways and changes will make the normal cells to attain certain malignant characteristics which include inappropriate proliferation in the absence of normal growth signals, indefinite self-renewal in a manner analogous to a stem cell, escape from programmed cell death, inhibition of differentiation, aberrant cell cycle checkpoint control and genomic instability [4].

Incidence and Prevalence

AML is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States with an estimated 18,860 new cases and 10,460 deaths anticipated in 2014 (Cancer Facts & Figures 2014). In the Indian scenario, even though there are not many published data in AML incidence and prevalence, it is noted that the median age diagnosis of AML is much lower when compared to the western population. The median age in Indian population is between 41-45 years (Phillip et al, Unpublished data, CMC, Vellore, Dunna, Rajappa et al. 2010, Abraham, Varatharajan et al. 2012)

Etiology

Most cases of AML is sporadic, characterized by acquisition of somatic mutations in hematopoietic progenitors that confer a proliferative ...

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...es the anti-leukemic activity of Ara-C [27].

Ribonucleotide Reductase (RR)

De-novo nucleotide biosynthesis pathway is shown to cross talk with Ara-C activation pathway through the enzyme ribonucleotide reductase (RR). dNTPs generated by RR acts as competitive inhibitor against the active metabolite Ara-CTP and prevents them from incorporating into the DNA. Furthermore, high intracellular dNTP pools inhibit dCK activity, thereby reducing Ara-C activation. The RR holoenzyme is a dimeric protein and comprises of large and small subunits, ribonucleotide reductase M1 (RRM1) and ribonucleotide reductase M2 (RRM2). In patients with advanced non small cell lung cancer treated with gemcitabine, a drug that has similar metabolic pathway like Ara-C, low RRM1 mRNA expression levels was associated with significantly longer median survival than those with high levels [28] [29].